Chapter 25: Therapeutic Drug Monitoring and Poisoning

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Welcome.

If you are a college student staring down a massive clinical biochemistry exam right now, just take a deep breath.

Yes, take a breath because you are in the exact right place today.

Consider this a special one -on -one tutoring session, deep dive.

We know clinical biochemistry can feel incredibly overwhelming.

Oh, absolutely.

It can feel like you're looking at this massive jigsaw puzzle, right?

And all the pieces are the exact same shape.

I remember that feeling perfectly.

Okay.

But we promise by the end of today's session, those pieces are gonna click together for you perfectly.

That is the overarching mission today.

It is.

We are pulling all our information directly from chapter 25 of the eighth edition of clinical biochemistry and metabolic medicine.

And the specific focus there is therapeutic drug monitoring and poisoning.

Exactly.

We're gonna walk you through the material in the exact order you need to learn it.

We'll break down the physiological pathways, the laboratory values.

The real world clinical cases too.

Right, the clinical cases so that you are fully prepared to just ace those exams.

Okay.

Let's unpack this starting right at the beginning with the absolute basics of drug monitoring

because let's say you give a patient a drug.

Why on earth do we need to keep drawing their blood to measure the concentration?

Right.

Why not just ask them how they feel?

Yeah.

Why not just see if it's working clinically?

It's a fundamental question and it will definitely be on your exams.

We monitor it for three main reasons.

First, to check compliance.

Meaning whether the patient is actually taking the medication you prescribed?

Exactly.

Second, to ensure the dose is high enough to be effective but not so high that it becomes toxic.

And third, to diagnose potential drug side effects or interactions.

But we have to make a vital distinction here, don't we?

We do.

There's clinical monitoring which is like taking a blood pressure reading after giving someone an antihypertensive.

You can see the result right there.

Right.

And then there's biochemical laboratory monitoring.

Biochemical monitoring is what we do when the clinical effect is impossible to measure precisely on the fly.

So we actually have to measure the plasma concentration of the drug itself.

That makes sense because you can't exactly just wait to see if a patient has a severe epileptic fit to decide if their anticonvulsant dose is high enough.

Exactly, you need concrete numbers.

But getting a drug into the plasma and keeping it at the right level,

it's quite a journey for that little pill.

It starts with absorption, doesn't it?

It does.

When a patient swallows a pill,

lipid soluble drugs pass through the cell membranes of the gut much faster than water soluble ones.

Right.

But the process is highly variable.

Things like gut motility or even just whether the patient just ate a really heavy meal, that can completely alter how much of the drug actually makes it into the bloodstream.

So if I give the exact same 50 milligram pill to a 250 pound man and a 50 pound child,

the drug concentration in their blood is gonna be wildly different just because of the container size, right?

Yes.

Is that what the textbook means by volume of distribution?

That is the perfect way to visualize it.

Think of it this way.

If you drop a teaspoon of dye into a puddle, the water turns incredibly dark.

Very constrained.

Right.

But if you drop that same teaspoon into an entire swimming pool, you barely even notice it.

Wow, okay.

So if you give a standard dose of a drug to a highly edematous patient, someone retaining a massive amount of fluid,

they have a huge volume of distribution.

The drug dilutes out, leading to unexpectedly low plasma concentrations.

Conversely, that small child has a very small volume of distribution.

Exactly.

If you don't adjust the dose for their specific weight, that standard pill could cause a lethal overdose.

And once the drug is actually in the blood, it doesn't just float around freely, does it?

The text talks a lot about plasma proteins, specifically albumin.

How does that factor into the biochemistry?

This is a major trap for students, so pay close attention here.

When a drug enters the blood, a large percentage of it will hitch a ride by binding to plasma proteins like albumin.

But here is the golden rule of pharmacokinetics.

Only the free unbound drug is biologically active.

The protein -bound fraction does nothing.

It does nothing.

It was just held in reserve.

Let me make sure I'm following this.

The standard lab assays we run usually measure the total concentration, meaning both the free drug and the protein -bound drug combined, right?

Correct.

So what happens if your patient has a condition like hepatic cirrhosis, where their liver is failing and they just aren't producing enough albumin?

If albumin is abnormally low, there are simply fewer seats for the drug to bind to.

This means a much larger percentage of the drug is left floating around in its free, highly active state.

Which means the total measured drug level on the lab report might look completely normal to the doctor?

Yes.

But the patient could actually be experiencing massive toxicity because the active portion is skyrocketing.

You've got it.

You must always interpret total drug levels in the context of the patient's albumin concentration.

That is such a critical clinical pearl.

It really is.

Now, moving beyond distribution, we have to look at how the body clears the drug out, which brings us to the concept of half -life.

That's the time it takes for the plasma drug concentration to drop by exactly half.

Yes, and it dictates when you should actually draw the portion's blood.

It generally takes about five half -lives for a drug to reach a steady state in the plasma.

Meaning the amount of drug going in balances the amount going out.

Precisely.

Therefore, you should almost never draw blood for therapeutic monitoring before those five half -lives have passed, or your data will be completely useless.

But the textbook mentions an exception to normal elimination rules, something called saturation kinetics.

Phenytoin is the classic example given.

What is happening biochemically there?

Well, normally, the rate at which your liver clears a drug increases as the plasma concentration increases.

It scales up.

But with phenytoin, the liver enzymes that metabolize it have a very low capacity.

They get overwhelmed or saturated very quickly.

They hit a wall.

Exactly.

Once those enzymes are working at maximum capacity, just a tiny increase in the prescribed dose causes the drug to pile up in the blood.

The plasma level suddenly spiked disproportionately, causing severe toxicity.

So we've talked about how tricky it is to keep drugs in that perfect Goldilocks zone.

Let's look at what happens when the stakes are literally life and death -like with cardiac drugs.

Take digoxin, for example.

Right, used for heart failure.

But it has a razor -thin therapeutic margin.

Digoxin is notorious in clinical biochemistry for exactly that reason.

Not only is the margin narrow, but its toxicity is intimately tied to a patient's electrolytes.

Potassium and calcium, mainly.

Yes.

If a patient develops hypokalemia low potassium or hypercalcemia, their heart muscle cells become exquisitely sensitive to digoxin.

They're at massive risk for fatal arrhythmias, even if their actual blood levels of the drugs look perfectly normal.

Which brings us to the first big clinical case in the chapter.

Imagine a 69 -year -old man who is prescribed digoxin alongside a diuretic.

He goes to the clinic, his blood is drawn, and his digoxin level comes back at a frightening 3 .3 micrograms per liter.

And the therapeutic range tops out at 2 .2.

Right, so the doctor is terrified.

He is heavily toxic.

But this is where understanding the metabolic timeline saves the day.

The clinical biochemistry team investigates and discovers the blood sample was taken a mere two hours after the patient swallowed his morning pill.

Ah, so the drug was still absorbing into the bloodstream from the gut, artificially inflating the number.

Exactly.

You cannot measure a drug while it is still peaking from the gastrointestinal tract.

So what did they do?

When they repeated the test at the proper six to eight hour trough level, meaning the lowest concentration just before the next dose is due,

the level was 1 .2 micrograms per liter.

Perfectly normal.

Perfectly normal.

Timing is everything.

We've talked about drugs that clear out in hours.

Are there drugs that do the opposite?

Or you take them and they just seem to stay in your system forever?

Amiodarone is the classic textbook example for that.

It's a powerful antiarrhythmic drug, but it has a massive half -life.

On chronic therapy, its half -life can be up to 100 days.

100 days?

Yes.

It hides out in the body's tissues and is metabolized by the liver, not the kidneys.

And there's a really specific side effect for amiodarone that professors love to test on, right?

Something to do with the thyroid.

That's right.

Amiodarone contains a huge amount of iodine, and it physically blocks the peripheral conversion of the thyroid hormone free T4 into the more active free T3.

Wow.

Because of this, it can cause severe thyroid dysfunction, sometimes hypothyroidism, and sometimes, paradoxically, severe thyrotoxicosis.

You must regularly monitor thyroid function tests for anyone on this drug.

Okay, let's shift gears to the anticonvulsants.

We already mentioned phenytoin and its dangerous saturation kinetics, but another major one is carbamazepine, which has a process called autoinduction.

Can you explain that?

Think of autoinduction like building up a tolerance to spicy food.

Carbamazepine is metabolized by specific liver enzymes, but the presence of carbamazepine actually stimulates the liver to produce more of those exact same enzymes.

So the more of the drug the liver sees, the more enzymes it builds to destroy it, meaning during the first month of therapy, the body gets so efficient at clearing the drug that the plasma levels just drop on their own.

That is the core of it.

You almost always have to increase the dose after the first month just to maintain the same therapeutic effect you had on day one.

The text also lists several other seizure meds.

There's Velprote, which is notably hepatotoxic, so liver function tests are a must.

Then there are some newer ones like lamotrigine, which stabilizes voltage -sensitive sodium channels.

But the one that really stood out is vigabatrin.

The book says plasma levels don't predict toxicity at all.

Why wouldn't a blood test help us there?

Because vigabatrin causes irreversible inhibition of its target enzyme in the brain.

It binds to the receptor and permanently breaks it.

Permanently.

Yes.

Even after the drug has completely cleared from the bloodstream, the effect lasts until the body can manufacture brand new enzymes.

So measuring the plasma concentration tells you absolutely nothing about the pharmacological effect happening inside the brain.

That makes so much sense.

Okay, let's talk about psychiatric drugs.

Lithium is a massive one for bipolar disorder, but biochemically it behaves totally differently than what we've discussed so far.

It does, primarily because lithium is a simple ion.

It is not protein -bound at all.

And because it distributes slowly across cell membranes, standard protocol demands you measure it exactly 12 hours after the evening dose to get an accurate reflection of the tissue levels.

And it has a terribly narrow therapeutic window, which leads us to case two.

A 40 -year -old woman on lithium therapy is admitted to the emergency department with severe confusion.

Her lab results are chaotic.

Let's break them down.

Her lithium level is deeply toxic at 2 .8 millimoles per liter.

Her sodium is incredibly high at 150 millimoles per liter.

And her TSH thyroid -stimulating hormone is elevated at 18 .7 milliunits per liter.

What is the cascade of failures happening here?

This case beautifully illustrates how a single toxic chemical disrupts multiple organ systems.

First, lithium is highly nephrotoxic.

It specifically causes nephrogenic diabetes insipidus.

Meaning it affects the kidney's ability to manage water.

Exactly.

It blocks the kidneys from responding to antidiuretic hormone.

The kidneys lose their ability to concentrate urine, leading to massive water loss.

And because she's losing so much pure water, the sodium left behind in her blood becomes highly concentrated, which explains the high sodium level of 150.

Correct.

But what about the high TSH?

That points directly to primary hypothyroidism, another classic consequence of lithium toxicity.

The drug directly damages the thyroid gland's ability to produce hormones.

Ah, so the pituitary gland screams at the thyroid by pumping out massive amounts of TSH trying to get it to work.

Her failing kidneys couldn't clear the lithium, the accumulating lithium damaged the kidneys further, and simultaneously shut down her thyroid.

It's amazing how one high lab value explains the other three.

Moving on to respiratory drugs and antibiotics.

Theophylline is used for severe asthma, but also for recurrent apnoea in newborns.

Yes.

And this is a great trivia fact from the text.

In infants, their metabolic pathways are so immature that they actually process theophylline into caffeine.

Which means if an infant shows signs of toxicity, you might need to run assays for both theophylline and caffeine to get the full picture.

But let's look at the aminoglycoside antibiotics, like gentamicin.

Here's where it gets really interesting, because the monitoring protocol for gentamicin is completely different from everything else we've discussed.

It is unique.

We don't just take one blood sample, we take two.

Why the extra work?

Because with gentamicin, the margin between curing a deadly infection and causing permanent harm is razor thin.

Toxic levels will destroy the kidneys and permanently destroy the patient's hearing ototoxicity.

So how do we manage it?

We draw a trough level and a peak level.

So the trough is drawn right before the next dose is due, when the drug should be at its lowest point in the body.

Right.

You must ensure the drug has sufficiently cleared the system so that adding the next dose won't push the patient into kidney failure.

Safety at the bottom.

And the peak.

Then, about an hour after the injection, you draw the peak level.

This proves the concentration actually spiked high enough in the blood to effectively kill the bacteria.

Efficacy at the top.

Wow.

Precision medicine.

Let's transition to organ transplants and cancer treatments.

The amino suppressants and cytotoxics.

The text highlights metotrexate, which is a folate antagonist.

It's starved cells of the folate they need to replicate DNA.

But if we give high doses to kill cancer, how do we stop it from completely destroying the patient's healthy bone marrow?

The clinical biochemistry intervention there is rescue therapy.

We administer phylinic acid, which is a form of folate that bypasses the biochemical blockade created by metotrexate.

So it swoops in and rescues the healthy cells.

Exactly.

You also have to ensure the patient maintains an alkaline urine pH, because metotrexate becomes highly insoluble in acidic urine and can precipitate, destroying the kidneys.

Another transplant drug mentioned is sicklosporin.

It inhibits T lymphocyte activation.

But processing its blood test has a major catch.

It's highly lipophilic and over half of it hides inside the red blood cells.

Which means you cannot just spin the blood tube in a centrifuge, throw away the red blood cells, and test the plasma like you do for most drugs.

Because you'd be throwing away half the drug.

Exactly right.

For sicklosporin, you must use a whole blood sample collected in an EDTA tube.

Before we hit the final section, we need to talk about pharmacogenetics.

Why do two patients given the exact same dose of a drug react completely differently?

It all comes down to how their metabolic enzymes are genetically coded.

A great example is isoniazid, a tuberculosis drug.

It is inactivated in the liver by a process called acetylation.

And people do this at different speeds?

Yes.

Some people are genetically coded to be slow acetylators.

Meaning the drug builds up to toxic levels much faster in their bodies than in someone who is a fast acetylator.

The textbook also highlights TPMT -phiopurine -methyltransferase.

This enzyme metabolizes the immunosuppressant azathioprine.

About 10 % of the population has a genetic deficiency in this enzyme.

And a tiny fraction, about 0 .3%, have no functional TPMT activity at all.

So if you give a standard dose of azathioprine to that 0 .3 % It can be catastrophically toxic to their bone marrow.

That is terrifying.

And we cannot forget the cytochrome P450 family.

Specifically the 2D6 phenotype.

Your genetic status there dictates how well you process various antiarrhythmics and antidepressants.

So the overarching lesson is that standard biochemical monitoring is required not just for the drug levels but for side effects too.

Exactly.

You always check potassium and urea in patients on ACE inhibitors.

And you always check creatine kinase or CK for muscle damage in patients taking statins.

All right, we have reached the final and arguably most intense topic.

Poisoning and overdoses.

What is the golden rule when approaching a potential overdose?

If a patient is brought in with an unexplained coma or they have bizarre lab results like a sudden unexplained metabolic acidosis or a wildly raised CK enzyme, you must suspect a drug overdose.

Even if the patient aggressively denies taking anything.

And the most heavily tested overdose in the world is paracetamol or acetaminophen.

This brings us to case three.

A 23 year old woman comes in with a paracetamol overdose.

Her labs show a massive ALT and enzyme marking liver damage at 881 units per liter.

And normal is under 42.

Exactly.

Her INR, which measures how well her blood clots is dangerously elevated at 3 .1.

What is the biochemistry destroying her liver?

When you take normal amounts of paracetamol, the liver easily detoxifies it.

But in a massive overdose, it produces a highly hepatotoxic metabolite.

The liver relies on a protective compound called glutathione to neutralize it.

But the overdose completely depletes the liver's glutathione reserves.

Right, without that shield, the toxic metabolite runs rampant, tearing apart the liver cells.

You see this in her sky high ALT representing raw hepatocyte destruction and her high INR showing the liver is so damaged, it has stopped manufacturing blood clotting factors.

The antidote is an IV infusion of N -acetylcysteine, which essentially replenishes that glutathione shield.

But how do doctors actually know when to give the antidote?

The textbook talks about a treatment graph, or a nomogram.

Think of the nomogram like a racetrack on a graph.

You plot the time since the patient swallowed the pills on the bottom axis and their blood paracetamol concentration on the side axis.

And if their specific dot lands above the danger line, you administer the antidote.

Yes, but the critical rule is you never measure paracetamol levels before four hours post ingestion because the pills are still dissolving and absorbing in the gut.

But the graph has two lines, right?

A normal line and a high risk line.

Yes, it does.

Some patients have less protective glutathione to begin with, like those who are severely malnourished from anorexia or chronic alcoholism.

Or they're on those enzyme inducing drugs we talked about.

Like the carbamazepine, which causes their liver to generate that toxic paracetamol metabolite much faster.

For these high risk patients, the threshold to start the antidote is much lower.

And in all cases, the antidote is most effective if started within a strict four to 20 hour window.

Let's quickly review the other specific antidotes you need to memorize for the exam.

For iron overdoses, which are tragic because kids often think the tablets are candy, we use dysphoriaxamine.

It acts as a chelator, binding the iron tightly so the body can pee it out.

For benzodiazepines, the antidote is flumizanil.

For opiate overdoses, which shut down breathing and cause respiratory acidosis, we use naloxone.

And for carbon monoxide poisoning, we use pure oxygen to physically force the CO off the hemoglobin molecules.

And we must mention the severe metabolic acidosis caused by drinking ethylene glycol, which is antifreeze or methanol.

The treatment for those is wild to me.

Wait, let me get this straight.

If someone drinks antifreeze, the medical scientifically backed treatment is to give them an IV of alcohol.

You literally get them drunk to save their life.

It sounds absurd, but the biochemistry is fascinating.

It relies on a concept called competitive inhibition.

The antifreeze itself isn't what kills you.

It's the toxic metabolites created when your liver's alcohol dehydrogenase enzyme breaks it down.

But that enzyme has a much higher affinity for normal ethanol.

If you flood the system with ethanol, the enzyme gets completely distracted processing the alcohol, ignoring the antifreeze entirely.

The antifreeze is then safely excreted through the kidneys without ever being converted into its toxic form.

That is brilliant.

Let's look at our final clinical scenario case for dealing with a very common overdose that unfortunately has no specific antidote, salicylate or aspirin.

A 24 -year -old woman took 4 ,300 -milligram aspirin tablets.

That's a massive dose.

Eight hours later, her arterial blood gas shows a pH of 7 .55, which is alkaline, and a low pica 2 of 4 .0 kilopascals.

Why does an acid overdose cause an alkaline pH?

This sequence of events is a guaranteed exam question.

Aspirin directly stimulates the respiratory center in the brain stem.

The patient immediately starts hyperventilating, blowing off massive amounts of carbon dioxide.

Because CO2 acts as an acid in the blood, losing all that acid causes an initial respiratory alkalosis.

Exactly.

That explains her alkaline pH of 7 .55 and her low CO2.

It doesn't stay alkaline, does it?

No.

As the toxicity progresses, salicylate enters the cells and uncouples oxidative phosphorylation.

Essentially, it forces the cell's power plants to run in severe overdrive, producing heat instead of useful energy.

And this massive metabolic failure generates lactic acid and keto acids, eventually dragging the patient into a profound metabolic acidosis.

Right.

Because there's no antidote, the treatment relies heavily on keeping the patient stable.

Sometimes doctors will use forced alkaline diuresis, making the urine alkaline, to help the kidneys pull the acidic drug out of the blood.

But there was a massive catch to that, right?

A very dangerous catch.

If you induce an alkaline diuresis, you force potassium into the cells and excrete it in the urine.

You must obsessively monitor the patient's plasma potassium because there is a severe danger of inducing a lethal acute hypokalemia.

So we've gone from absorption to half -lives, to liver enzymes, to toxic overdoses.

If we connect this all to the bigger picture, the journey through this material proves that clinical biochemistry is not just about memorizing random reference ranges, it is about understanding the metabolic narrative of a molecule in the human body.

It's incredible how it all ties together.

It is.

It is understanding how the speed of absorption, the volume of distribution, the binding to albumin, the half -life, and the patient's unique genetic code all interact to dictate whether a chemical acts as a life -saving cure or a lethal poison.

You're not just looking at a number on a lab printout.

You are looking at the exact metabolic status of the patient sitting in front of you.

So what does this all mean for the future of medicine?

We'll leave you with this provocative thought to ponder while you review your notes.

As we continue to map the human genome, mapping out every variation in TPMT and cytochrome P450, will the entire concept of a standard dose completely disappear in our lifetimes?

Will every single prescription eventually be perfectly mathematically tailored to your specific DNA?

On behalf of both of us, a warm thank you from the Last Minute Lecture Team for tuning in.

Good luck with your studies.