Chapter 30: Drugs for Pain, Inflammation, and Arthritic Disorders

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Hello and welcome back to the Deep Dive.

Today, we are shifting gears a little bit.

We're pushing aside the articles, the news clippings, all the opinion pieces, and we are cracking open the textbook.

That's right.

We are going into what we like to call last minute lecture mode.

We know exactly who's listening today.

We do.

You're likely a pharmacy student, a med student.

Maybe you're in a nursing program and you have a pharmacology exam.

Just, you know, stare you in the face.

You don't need fluff.

You need to understand the drugs.

Specifically, we are tackling chapter 30 of Brenner and Stevens Pharmacology, the sixth edition.

And the topic is a big one.

Drugs for pain, inflammation,

and arthritic disorders.

It's a massive chapter.

I mean, we're talking about the drugs that feels like half the population is taking at any given moment.

But here's our mission statement for this session.

May it on us.

We are going to decode this text page by page, strictly in order.

And that's the key.

No confusing anecdotes from, you know, 1985 that aren't going to be on the test.

No off -label uses that are just going to trip you up.

Just the source material.

Just the text.

We have three main mountains to climb today.

Okay.

What are they?

Mountain number one, the NSAIDs, nonsteroidal anti -inflammatory drugs.

Right.

Your ibuprofen, aspirin, all those household names.

Got it.

Mountain number two, the DNARD -AIDS.

That stands for disease modifying anti -rheumatic drugs.

These are the heavy hitters for autoimmune disease.

And mountain three.

Mountain number three, the gout agents.

A very specific, very painful condition with some really interesting drugs.

It sounds manageable when you list it like that, but I know the biochemistry in this chapter gets pretty heavy.

So let's clear the ducks.

Open your mental textbook to the very first section.

The pathophysiology of rheumatoid arthritis, or RA.

You really can't understand the drugs if you don't respect the disease.

And Brenner and Stevens start by defining RA very, very specifically.

It is an autoimmune disorder of unknown cause.

Unknown cause.

That always sounds a bit scary in medicine, doesn't it?

Means we don't know who started the fire.

We just know the house is burning down.

That's a perfect analogy.

And it's not rare.

The text makes a point of noting it affects two to three percent of the U .S.

population.

But here's the demographic fact that shows up on almost every board exam I've ever seen.

What's that?

It is three times more common in women than in men.

Three times.

Wow.

And it usually hits between ages 40 and 60.

So clinically, how do we distinguish this from just, you know, my knee hurts because it's raining?

Great question.

The hallmark, the absolute defining feature, is symmetry.

Symmetry.

In RA, if your right wrist is inflamed and painful, your left wrist usually is too.

It loves the small joints, the hands, the wrists, the feet.

But because it's autoimmune, it's systemic.

It's not just a joint disease.

It is a whole body inflammation.

Right.

The text mentions these extraarticular manifestations, which is, you know, fancy talk for stuff happening outside the joints.

Exactly.

You'll see things like vasculitis.

That's inflammation of the blood vessels.

You might see splenomegaly, which is an enlarged spleen.

And you get these things called rheumatoid nodules.

What are those?

They're little bumps that form under the skin, usually on what we call the extensor surfaces, like the back of the elbows or your forearms.

Okay.

I want to look at figure 30 .1 in the source material now because this is the diagram of the whole mechanism.

To me, it just looks like a warm -up.

It is a warm -up.

And you absolutely need to memorize the generals in this army because the drugs we're going to talk about later are basically assassins designed to target these specific generals.

Okay.

So walk us through the cascade.

Who fires the first shot?

Well, it starts with some kind of antigen.

The body thinks it's an invader, but we don't know what it is.

That activates the tendritic cells.

You can think of these as the scouts.

They see the enemy.

They see the enemy and they present the intel to the T cells.

And T cells are the commanders.

Correct.

So once the T cells are activated, they call in the air support.

They activate B cells.

Now B cells are little factories.

They just start pumping out antibodies, specifically something you'll hear a lot about called rheumatoid factor.

And while all that's happening, the macrophages show up.

Yes.

And this is the crucial moment in the battle.

The T cells and the macrophages start screaming at each other, chemically speaking.

They release a flood of cytokines.

This is the cytokine storm we hear about.

Precisely.

If you remember nothing else from this pathophysiology section, remember these three names.

Tumor necrosis factor alpha.

TNF alpha.

Interleukin 1, or IL -1.

And interleukin 6, IL -6.

I have a very strong feeling those three names are going to be the targets for some very expensive drugs later on in this conversation.

You are spot on.

Those cytokines are the destructors.

They stimulate the release of prostaglandins and other cytotoxins.

This causes the synovial tissue inside the joint to proliferate.

It just starts growing wildly.

And it essentially starts eating the cartilage and the bone.

That's a terrifying image.

The body literally eating its own joints from the inside out.

It is.

And that leads us directly to the treatment strategy, which the text divides into two clear lanes.

Lane 1, put out the fire.

That's for immediate symptom relief with NSAIDs.

Lane 2, stop the army.

That's using the DRNs to actually interfere with those T cells and cytokines and stop the progression of the disease.

Now before we open the drug cabinet, the chapter takes a little detour to define two other enemies.

Osteoarthritis, or OA, and gout.

I think people confuse RA and OA constantly.

What's the deep dive distinction here?

It's simple.

Think of RA as autoimmune attack and OA as wear and tear.

Okay, wear and tear.

Osteoarthritis is degenerative.

It's not the body attacking itself.

It's the body just wearing out from use over a long time.

The text has a stat here that really blew my mind.

It says radiographic evidence.

So evidence on an X -ray of OA is found in most people over age 65.

It is almost universal if you live long enough.

It's the price of a long life in some ways.

And it hits the weight -bearing joints, your knees, your hips, your spine, the cartilage, the cushions, the bones, it thickens, then it starts to split.

And eventually it just wears away completely until you have bone grinding on bone.

Which sounds incredibly painful.

And since it's not autoimmune, the treatment approach is different.

The treatment for the pain is similar.

We still use NSAIDS, but we don't use those heavy -duty immune suppressors, the DMARDS.

We focus more on things like physiotherapy, splinting the joint, weight loss to take pressure off.

But there is one drug mentioned here that I just love for the trivia value alone.

Sodium hyaluronate.

Oh, yeah.

I highlighted this one.

The brand name is Supert.

And the source of this drug is, let's say, unique.

It really is.

It's often extracted from chicken combs.

You mean the red fleshy thing on a reester's head?

That is the one.

It's full of hyaluronate.

They purify it, process it into a sterile viscoelastic solution, and the doctor injects it directly into your knee.

What does it do?

It basically acts as a synthetic lubricant and a shock absorber.

It's like getting an oil change for your joint.

That is absolutely incredible.

Okay, let's pivot quickly to gout.

We'll do a deep -dodge on the gout drugs later, but what's the basic physiology?

Gout is chemistry gone wrong.

It's a metabolic disorder.

Your body has too much uric acid in the blood.

That's called hyperuricemia.

When the concentration gets too high, that uric acid can't stay dissolved anymore.

It precipitates out of the blood, and it forms crystals.

Monosodium urate monohydrate crystals, to be exact.

Exactly.

And you have to imagine these crystals are like microscopic needles.

They lodge in the joints classically, the big toe, and the immune system sees them and just freaks out.

It mounts a massive attack against the crystals, causing incredible acute pain and inflammation.

The text lists the risk factors, obesity, alcohol,

and interestingly, cancer chemotherapy.

Why chemo?

Think about what chemotherapy does at a cellular level.

It kills cells, lots of them, very quickly.

Okay.

When a cell dies and bursts open, it releases all of its contents.

That includes its DNA and RNA.

Those nucleic acids are made of building blocks called purines.

The body breaks down purines into uric acid.

So massive cell death leads to a massive spike in uric acid.

A huge spike, which can trigger a gout attack.

Okay.

We know the diseases now.

RA, OA, gout.

Now, let's get into the pharmacology.

We're starting with probably the most common drugs in the entire world.

The NSAIDs.

Non -steroidal anti -inflammatory drugs.

Aspirin, ibuprofen, naproxen.

To understand how they work, you have to look at figure 30 .2 in the text.

We need to talk about the arachidonic acid pathway.

This is classic biochemistry.

Walk us through it.

Okay.

So imagine a cell membrane.

It's made of phospholipids.

When that cell is injured, an enzyme called phospholipase A2 comes along and it snips off a piece of the membrane's fatty acid.

That piece is arachidonic acid.

So arachidonic acid is the raw material for inflammation.

It's the fuel.

Now, floating around inside the cell is another enzyme called cyclooxygenase, or we just call it COX.

COX.

The COX enzyme grabs that arachidonic acid and churns it through a little chemical tunnel, converting it to prostaglandins.

And prostaglandins are the bad guys in this story?

In this context, yes, they are.

Prostaglandins do three things you really hate when you're injured.

One, they sensitize your nerve endings so you feel pain much more intensely.

Two, they dilate your blood vessels, which causes the redness and swelling of inflammation.

And three, they travel up to the brain and they cause fever.

So the entire NSAI strategy is just jam the machine.

Exactly.

NSAIs enter that CanOX enzyme tunnel and they just block it.

They sit in the active site.

If the enzyme is blocked, arachidonic acid can't get through.

No prostaglandins are made, and so no pain, no inflammation, no fever.

Speaking of fever, the text explains the thermostat analogy.

I found this really helpful for understanding it.

It's a great analogy.

Your hypothalamus in your brain has a set point for temperature.

Normally, it's 98 .6 degrees A or 37 degrees C.

Right.

When you get an infection, bacterial toxins cause your immune cells to release cytokines.

Those cytokines travel to the brain.

They tell the hypothalamus to release prostaglandins.

And those prostaglandins physically turn the dial up.

They say the new normal is one or two too.

So that's why you feel cold and you get the shivers because your body thinks its normal temperature of 98 is suddenly too low.

Precisely.

It's trying to get up to the new set point.

When you take an NSAI, you stop the prostaglandin production in the brain.

The hypothalamus realizes, oh wait, the dial should be back at 98 .6, and it activates cooling mechanisms like sweating to bring you down.

But this is a key point in the text.

NSAIs generally don't lower your temperature if it's already normal.

That's right.

They don't turn on the AC if the house is already cool.

They just fix a broken thermostat that's set too high.

Now we absolutely have to talk about the tale of two enzymes.

KoX1 and KoX2.

This is the holy grail of this chapter, isn't it?

It is the single most important concept for understanding all the side effects.

The KoX enzyme actually has two major isoforms.

You can think of them as two twins.

Yeah, twin one.

KoX1.

The text calls it constitutive.

Think of KoX1 as a housekeeper.

It's always working constitutively in almost all of your tissues.

It's making good prostaglandins.

Good prostaglandins.

Yes, prostaglandins that do helpful things.

For example, they produce the protective mucus lining in your stomach so that your stomach acid doesn't burn a hole in it.

They also help your platelets stick together.

A process called aggregation.

So you can form clots and not bleed to death from a paper cut.

So KoX1 is our friend.

We need it.

We definitely need it.

Twin two is KoX2.

This is the inducible one.

It's usually asleep.

It's not doing much.

But when there is inflammation or injury, the cell gets a signal to wake it up.

KoX2 then starts pumping out the prostaglandins that cause pain and swelling.

So in a perfect world, we would design a drug that only blocks KoX2.

Stop the pain, but leave the housekeeper KoX1 alone.

That is the billion dollar dream.

But the traditional NSAIs like ibuprofen, naproxen, aspirin, they are non -selective.

They're blunt instruments.

They block both twins.

And that one fact explains basically every side effect listed in the book.

Every single one.

You block KoX2 and the pain goes away.

But you also block KoX1 so the protective stomach nuchus stops being made.

And you get ulcers.

And your platelets stop working properly.

So you bleed more easily.

It all connects.

It all connects back to KoX1 versus KoX2.

Before we get to the specific drugs, there's a little note here about acetaminophen, you know, Tylenol.

The text suggests it might work on a third twin.

This is the big mystery of acetaminophen.

Everyone knows it kills pain and it kills fever.

But it does almost nothing for inflammation.

If your knee is swollen up like a balloon, Tylenol won't shrink it.

So it can't be working on KoX2 and the knee.

Probably not.

The leading theory is that it preferentially targets a splice variant called KoX3, which is found mostly in the brain and central nervous system.

So it stops the perception of pain and the fever mechanism in the head.

But it doesn't really touch the KoX enzymes out in the body where the inflammation is happening.

That's fascinating.

Okay, let's get into the specific drugs, starting with the absolute grandfather of pharmacology, aspirin.

The salicylates.

It's been around since 1899, derived from Willow Bark.

Yeah.

But chemically, aspirin is a complete rebel.

Every other NSAID we'll talk about sits in the KoX enzyme, blocks it for a while and then it floats away.

It's a reversible inhibition.

But not aspirin.

Aspirin is an irreversible inhibitor.

It walks into the KoX enzyme and it chemically welds itself to the active site.

It acetylates a serine residue.

That enzyme is dead.

It will never work again.

The cell has to build a whole new one.

The text really emphasizes that that's why aspirin is used for preventing heart attacks, whereas a drug like ibuprofen isn't.

Correct.

It's all about the platelet.

Platelets need their KoX1 enzyme to produce something called thromboxane A2, which makes them sticky and allows them to form clots.

Okay.

If you take ibuprofen, the platelets KoX1 is blocked for a few hours, but then the ibuprofen leaves and the platelet recovers.

But if you take aspirin, you permanently kill the KoX enzyme inside that platelet.

And since platelets don't have a nucleus.

They can't build new enzymes.

That platelet is disabled for its entire lifespan, which is about 10 to 14 days.

That is why a single baby aspirin a day works as a permanent blood thinner.

You're effectively taking out a fresh batch of your platelets every single day.

That's a powerful mechanism.

But aspirin isn't safe for everyone.

There is a massive like red box warning in this chapter regarding children.

Ray syndrome.

And if you are studying, listening very closely to this, never ever give aspirin to a child or a teenager who has a viral infection.

Like the flu or chickenpox.

Exactly.

If a kid has chickenpox and you give them aspirin for the fever, it can trigger ray syndrome.

This causes fulminant liver hepatitis and cerebral edema.

Massive brain swelling.

It is very often fatal.

So stick to Tylenol or ibuprofen for the kids.

Period.

Now let's talk about aspirin toxicity.

Specifically the elimination kinetics.

The text mentions it switches to zero order elimination.

This sounds like math, which frankly scares me.

It's not as bad as it sounds.

Think of it like a bucket with a small hole in the bottom.

Normally with what we call first order kinetics, the more water you pour in, the faster it drains out.

The pressure pushes it through more quickly.

That's how low -dose aspirin works.

But at high doses, for arthritis for example.

The hole gets clogged.

The liver enzymes that break down aspirin get completely saturated.

It switches to zero order.

And that means only a fixed amount can leave per hour, say 10 milligrams per hour, no matter how much is in the blood.

So if I take a huge dose, the bucket overflows almost immediately because the drain can't keep up.

Exactly.

A small increase in dose can lead to a massive, dangerous spike in your blood concentration because the exit door is jammed.

The system is overwhelmed.

So what does an aspirin overdose actually look like?

Figure 30 .3 in the book is a bit terrifying.

It starts with a classic sign, tannitus, ringing in the ears.

If your patient on high -dose aspirin says their ears are ringing, you need to back off the dose, then it gets very weird.

Hyperventilation.

You start breathing too fast.

Solicilates directly stimulate the respiratory center in your brain.

You start to pant.

You blow off all your CO2.

This causes a condition called respiratory alkalosis.

OK.

But then as the drug itself, which is an acid, accumulates, the body crashes into a severe metabolic acidosis.

You get a high fever and eventually you can go into shock.

It's a medical emergency.

And the antidote or the treatment?

You have to help the kidneys flush it out.

Aspirin is a weak acid.

So we give the patient intravenous sodium bicarbonate to make their urine basic or alkaline.

The basic urine acts like a chemical magnet, pulling the acidic aspirin out of the blood and trapping it in the pee so it can't get reabsorbed back into the body.

That's incredible biochemistry at work.

Now let's look at the drug everyone thinks is completely safe.

Acetaminophen.

Tylenol.

And it is very safe if you stay within the recommended dose.

But the mechanism of liver toxicity is something every single health sciences student must be able to draw on a napkin from memory.

OK.

Let's draw it then.

This is figure 30 .4.

Normally when you take Tylenol, your liver takes the molecule and attaches a tag to it.

Either a sulfate group or a glucuronide group.

This process is called conjugation.

It makes the drug harmless and water soluble and you just pee it out.

But there's a side door pathway?

There is.

The CYP450 enzyme system.

A tiny percentage of Tylenol, maybe 5%, goes through this pathway and is turned into a highly toxic metabolite called NAPQI.

NAPQI.

Even the name just sounds toxic.

It is.

It's a reactive keynote.

It is designed to bind to proteins and kill liver cells.

Now normally your liver has a superhero antioxidant called glutathione.

Glutathione's job is to find NAPQI and neutralize it instantly.

It tackles it, renders it harmless, no harm done.

But in an overdose?

In an overdose, you take so much Tylenol that you produce a massive amount of NAPQI all at once.

You completely run out of glutathione.

The superhero is dead.

NAPQI then builds up unchecked and it just starts destroying liver cells.

That's hepatic necrosis.

And this is why the antidote is a drug called acetylcysteine?

Yes.

N -acetylcysteine or NAC, it acts as a precursor.

It gives the liver the raw materials it needs to build more glutathione very, very quickly.

You're essentially restocking the shells so the liver can fight off the NAPQI.

That is a life -saving mechanism to understand.

Okay.

Let's round out the common NSAIDS with the propionic acid derivatives.

We're talking about ibuprofen and aproxen.

What's the main difference between,

say, Advil and Alev?

It's one thing and one thing only.

Half -life.

That's it.

Yeah.

How long it lasts.

Ibuprofen, which is Advil or Motrin, has a short half -life of about two hours.

That's why you have to pop them every four to six hours for sustained relief.

Naproxen, which is Alev, has a much longer half -life of about 14 hours.

So that's your twice -a -day dosing that they advertise.

Exactly.

It's purely a convenience factor.

From a mechanism and side effect standpoint, the stomach upset, the potential kidney stress if you're dehydrated, they are virtually identical.

One last NSAID to flag before we move on.

Ketorolac or Toradol?

Ah, the hospital NSAID.

It's often given as an injection.

It is incredibly potent.

The pain relief is comparable to morphine for some types of pain, but without any of the high or the respiratory depression.

It's fantastic for things like kidney stones or post -op pain.

But there is a huge, bolded warning in the text.

Do not use for more than five days.

Why the hard stop?

It is famously toxic to the kidneys.

All NSAIDs can be, but Ketorolac is particularly harsh.

It can clamp down on the blood vessels that feed the kidneys, the affluent arterioles.

If you use it for too long, you can cause acute renal failure.

So five days is the absolute hard stop.

No exceptions.

Okay.

We mentioned earlier the dream of a drug that only blocks CoX2.

Let's talk about section five.

The selective CoX2 inhibitors, the coxibs.

This was the billion -dollar idea of the late 90s.

If we can spare CoX1, we can spare the stomach.

We can get all the anti -inflammatory benefit without the ulcers.

It sounds perfect, but the text describes a rise and fall.

What happened to Vioxx?

Vioxx or Rofocoxib and another one called Bextra, Valdicoxib, were absolute superstars.

Until we realized they were causing heart attacks and strokes.

They were pulled from the market in a huge scandal.

Why would blocking only CoX2 hurt the heart?

It seems counterintuitive.

It's all about balance again.

It turns out that CoX2 in the lining of your blood vessels produces something called prostacyclin, which is protective.

It keeps blood vessels open and it tells platelets to calm down.

Meanwhile, CoX1 in your platelets is producing thromboxane, which clamps vessels and makes platelets sticky to form clots.

So if you create a drug that blocks the calm down signal from CoX2, but leaves the clot now signal from CoX1 running you.

You tip the whole scale toward clotting.

Precisely.

And that's why we saw an increase in cardiovascular events like heart attacks and strokes.

But one of these drugs survived.

Celecoxib or Celebrex?

It's the last man standing of that original class.

It does cause significantly fewer stomach ulcers than ibuprofen or naproxen, which is a huge win for certain patients, especially the elderly.

But it's not misc -free.

Not at all.

If you look at the package insert for Celebrex, it carries a prominent boxed warning for cardiovascular risk.

It's the same warning all non -aspirin NSIs now carry, but it's a legacy of what happened with biox.

The risk is still there.

There's a really interesting fit note in this section about surprising uses.

The text links CoX2 to Alzheimer's and colon cancer.

How does that work?

This is fascinating science.

We know that chronic inflammation seems to be a driver in the pathology of Alzheimer's disease.

And CoX2 is also heavily involved in angiogenesis.

That's the growth of new blood vessels.

Which tumors need to grow and survive?

Exactly.

Tumors need a blood supply.

So the theory was if you block CoX2, you could potentially slow the progression of Alzheimer's or maybe starve a tumor.

So could you use Celebrex to prevent colon cancer?

There is good evidence it can prevent the formation of colon cancer polyps in high -risk individuals.

But because of the cardiovascular risks we just talked about, we generally don't use these drugs just for prevention in the general population.

The risk -benefit ratio just doesn't quite work out.

All right.

We have conquered mountain one, the NSAIs.

Now let's hike up mountain two, the DMARDS.

Disease Modifying Anti -Romantic Drugs.

This is where we stop just treating the symptoms and we start treating the underlying disease itself.

And the key difference, as you said earlier, is time.

Yes.

An NSAID works in an hour.

The DMARD can take weeks, sometimes months, to show a full effect.

Their goal is to stop that joint erosion we talked about way back in the intro to actually halt the damage.

The chapter starts with a bit of a history lesson.

Gold salts.

This is really old -school pharmacology.

Back in the day, the famous scientist Robert Koch discovered that gold salts could inhibit the growth of the bacteria that causes tuberculosis.

Okay.

And for some reason, people thought rheumatoid arthritis looked a bit like TB, so they just started injecting people with gold.

Then did it work?

Shockingly, yes.

It has an immunomodulating effect, but the toxicity profile is just wild, horrible rashes, kidney damage, terrible mouth sores, a condition called stomatitis.

We rarely, if ever, use it now because we just have so many safer, better drugs.

Like glucocorticoids?

Prednisone.

Prednisone is the ultimate bridge therapy.

Imagine you diagnose a patient with severe RA today.

You start them on a proper DMARD, but you know that's going to take six or eight weeks to really kick in.

What do they do in the meantime?

They just suffer.

No.

You give them a short course of prednisone.

It works almost immediately to crush the inflammation.

The mechanism is actually upstream of the NSAIDs.

It induces a protein in the cell called lupacortin.

And lupacortin blocks phospholipase A2.

Exactly.

Remember back to figure 30 .2.

Phospholipase A2 is the very first enzyme that snips off arachidonic acid from the cell membrane.

If you block that, you stop the entire inflammatory cascade.

No prostaglandins, no leukotrienes, nothing.

It sounds like a perfect drug.

Why not just stay on prednisone forever?

Because long -term systemic steroid use is a nightmare.

It causes osteoporosis, diabetes,

massive weight gain, thin skin that bruises, cataracts, and a huge risk of serious infections.

So we use them strictly as a bridge to get to a safer drug or for short -term control of an acute flare.

Okay.

So what is that safer long -term anchor drug?

The text calls it the gold standard.

Methotrexate.

If you are a student, you should highlight, circle, and put stars next to methotrexate.

It is the first -line therapy for moderate to severe RA.

So how does it work?

It's not blocking cytokines directly.

No, it works on a much more fundamental level.

It inhibits an enzyme called dihydrofolate reductase.

This enzyme is critical for recycling folate in the cell.

And without active folate, you can't build new DNA.

So the immune cells, which are dividing rapidly, can't replicate.

Exactly.

It preferentially targets those rapidly dividing cells, the activated T cells and B cells that are causing all the problems in the joint.

It just stops the army from building new soldiers.

But stopping DNA synthesis sounds, well,

broadly toxic.

It is.

At high doses, methotrexate is a chemotherapy drug used for cancer.

For RA, we use much lower once -a -week doses.

But you still have to monitor for toxicity very carefully.

It can cause liver toxicity, lung fibrosis, and bone marrow suppression.

And what about pregnancy?

Absolutely not.

It is a potent teratogen.

It can cause abortion and severe birth defects.

You have to ensure a patient is not pregnant and is on reliable contraception before you even think about starting methotrexate.

Next on the list of non -biologic DMARs is leflunamide.

This is a common alternative, especially if a patient can't tolerate methotrexate.

It works on a similar principle, but a different enzyme.

It inhibits dihydrogenase.

That's a mouthful.

It is.

But all you need to know is that it stops pyrimidine synthesis.

Again, no pyrimidines, no DNA, no T cell proliferation.

The side effect profile is a bit different, though.

Diarrhea is very common, and so is alopecia or hair loss, also teratogenic.

And we have a really interesting one, hydroxychloroquine.

This is an anti -malarial drug, right?

Yes.

It's generally considered one of the milder DMARs.

It doesn't typically cause the bone marrow, liver, or kidney damage that you see with methotrexate.

So what's the downside?

It's slow, very slow.

The book says it can take three to six months to see the full benefit.

And there is one very specific, very scary side effect you must know.

What's that?

Ocular toxicity.

It can bind to the melanin pigment in the retina and cause irreversible vision loss.

Patients on this drug need a baseline eye exam before they start, and regular checkups with an ophthalmologist to catch any changes early.

Wow.

OK, now we enter the modern era of RA treatment, the biologics.

The text refers to them as the MABs and the CEPs.

These are the targeted missiles.

Remember those key cytokines from the intro, TNF -alpha IL -1, IL -6?

These drugs are proteins that are bioengineered to hunt down and neutralize those specific targets.

Let's focus on the TNF -alpha blockers first.

There's a T -intercept, infliximab, adolumimab,

a whole bunch of them.

TNF -alpha is really the master regulator of the inflammation in RA.

So blocking it is a very effective strategy.

E.

T -intercept is interesting.

It's a fusion protein.

It's basically a fake TNF receptor fused to a piece of an antibody.

It just floats in the blood.

TNS binds to it instead of the real receptor, and it gets neutralized.

Like a decoy and infliximab.

That's a monoclonal antibody, a MAB.

Specifically, it's a chimeric antibody part mouse, part human.

It binds directly to the TNF molecule itself and prevents it from working.

Adolumimab, or Humira, is a fully human antibody that does the same thing.

These sound like miracle drugs for patients.

They can be life -changing, incredibly effective.

But you are deliberately tampering with a key part of the immune system's defense grid.

TNF is used by the body to wall off infections,

particularly tuberculosis, or TB.

So if you block TNF?

A latent TB infection that a person has had for years can suddenly wake up, reactivate, and spread throughout the body.

You must screen every single patient for TB before starting one of these biologics.

And there's another warning about lymphoma?

Yes, there's a small but real increased risk of lymphoma.

It makes sense.

If you're suppressing the immune system's surveillance, you might increase the risk of a cancer slipping through.

The text also lists interleukin inhibitors.

And Echinra blocks IL -1, and Tosolizumab blocks IL -6.

Same concept, just a different cytokine target.

If the TNF blockers don't work for a patient, or if they stop working, you might switch to one of these.

Tosolizumab, which blocks the IL -6 receptor, is often used in patients who have failed methotrexate.

And finally, in this biologic section, there's a drug that targets the conversation between the immune cells themselves.

Abaticept.

This one is very cool.

It's a costimulation modulator.

For a T cell to get fully activated and angry, it needs two handshakes from the dendritic cell.

Abaticept looks like one of the handshake partners, so it gets in the way and blocks that second handshake.

It basically tells the T cell, stand down, false alarm.

That's a clever mechanism.

The newest class mentioned in the chapter involves small molecule inhibitors, the JEC inhibitors.

Right, Upadesatinib and Beresatinib.

All the biologics we just discussed are proteins, which means they have to be injected or infused.

The JEC inhibitors are small molecule pills you can take by mouth.

That's a huge advantage for patients.

It's a massive advantage.

And they work inside the cell.

When a cytokine binds to its receptor on the outside, the receptor uses an intracellular signaling pathway called the Janus kinase or JEC pathway.

It's like the phone line from the receptor to the nucleus.

These drugs get inside and cut the line.

Before we leave DMRs, there are two quick old school mentions,

sulfasalazine and penicillin.

These are sort of backups.

Sulfasalazine is a Frankenstein drug.

It's a sulfa antibiotic chemically linked to a salicylate.

The bacteria in your colon break it apart.

It's used for both RA and ulcerative colitis.

Penicillin is actually a copper chelator used for a genetic condition called Wilson's disease.

But it was found to have some efficacy in RA.

They're not first line choices anymore.

We have summited mountain two, now for the final stretch.

Mountain three,

the drugs for gout.

To understand these, we have to visualize figure 30 .5, the uric acid pathway.

Okay.

It starts with purines, which come from the breakdown of DNA and RNA.

Those get broken down into a substance called hypoxanthine.

Right.

Then an enzyme called xanthine oxidase comes along and it turns hypoxanthine into xanthine.

And then that same enzyme, xanthine oxidase, works again to turn xanthine into uric acid.

Correct.

And uric acid is the end product that forms those painful crystals.

So to prevent gout, we have three basic strategies.

Strategy one, make the kidney pee out the uric acid faster.

These are the uricocerex, like probenicid.

Exactly.

Probenicid works in the kidney tubules.

It inhibits the transporter protein that's responsible for reabsorbing uric acid back into the blood.

It basically locks the door so the uric acid is forced to stay in the urine and get flushed out.

But the book highlights a massive interaction here with aspirin.

Yes.

This is a classic test question.

Aspirin totally messes with probenicid.

In fact, low -dose aspirin on its own actually causes the body to retain uric acid.

So if a gout patient takes a baby aspirin, they might actually trigger an attack.

They should stick to other pain relievers.

OK, so that's strategy one.

What's strategy two?

Strategy two, stop the factory.

We block the production of uric acid in the first place.

And we do that by targeting the enzyme.

We target xanthine oxidase.

This is the most common preventative strategy.

And the drug is allopurinol.

Allopurinol.

It acts as a competitive inhibitor of xanthine oxidase.

And it just shuts the enzyme down.

The pathway stops at xanthine and hypoxanthine, which are much more water -soluble and easy for the kidneys to pee out.

You never even make the problematic uric acid.

Are there major risks with allopurinol?

Yes.

Hypersensitivity reactions.

Rashes can be very severe, even life -threatening, like Stevens -Johnson syndrome.

If a patient on allopurinol develops any kind of rash, you stop the drug immediately.

There's a newer drug, Phobuxostat.

Which works the same way, but is a bit more selective.

And strategy three.

This one sounds intense.

Bring in the heavy machinery to break down the uric acid that's already there.

This is for very severe cases.

The drug is paglotticase.

Now, most other mammals have an enzyme in their body called uricase that breaks down uric acid into a harmless substance called allantoin.

Humans, for some evolutionary reason, lost the gene for that enzyme.

So we just synthesized it.

We made a recombinant version of it.

Paglotticase is that uricase enzyme.

We inject it into the patient, and it just dissolves all the uric acid in their body.

It's used for chronic refractory gout that won't respond to anything else.

But it's a foreign protein, so the risk of a severe allergic reaction is quite high.

Okay, that covers prevention.

But finally, we have to treat the acute attack.

Prevention is great, but what do you do if your big toe is currently red, swollen, and throbbing?

You need to stop the inflammation and nobu.

You can use a high dose of an NSAID, specifically endomethacin is the classic choice because it's so potent.

Or you use a very unique drug called colchicine.

Colchicine, the mechanism of action here is one of my absolute favorites in the whole book.

It's so visual.

Colchicine works by binding to a protein called tubulin.

Tubulin is the building block for microtubules.

Which are like the skeleton of the cell.

They are the cell's internal skeleton and highway system.

And white blood cells, the granulocytes, need that skeleton to move.

They crawl toward the site of inflammation using their microtubules.

Colchicine gets into the cell and it causes the microtubules to fall apart.

It dissolves the skeleton.

So the white blood cells are just frozen in place.

They can't migrate into the joint to cause more inflammation?

You're freezing the army.

But that microtubule skeleton is also needed for rapidly dividing cells like the ones that line your gut.

So colchicine has absolutely notorious side effects.

Nausea, vomiting, and severe cramping diarrhea.

The text politely calls them GI disturbances.

But clinically,

the old saying was, you take the drug until the pain stops or the diarrhea starts, whichever comes first.

Wow.

We have covered a tremendous amount of ground.

From the irreversible binding of aspirin to the frozen microtubules of gout.

Let's try to synthesize all of this.

What are the top five takeaways for the student who is listening right now, cramming for their exam?

Okay, let's do it.

Takeaway number one, mechanism matters.

NASADs work by blocking the KEOX enzyme.

Remember, KEOX1 is the stomach protector.

KEOX2 is the pain maker.

If you block both, you're going to get ulcers.

Takeaway number two.

Aspirin is special.

It's the only irreversible COX inhibitor.

That's why it works for heart protection.

But you have to be aware of Ray syndrome in kids and that tricky zero order kinetics in an overdose.

Takeaway number three.

Acetaminophen is not an NSAA.

It spares the gut and the platelets.

But it targets the liver in an overdose.

For your exam, the villain is NAPQI and the hero you need to replenish is glutathione.

Takeaway number four.

DMARDS play the long game.

Methotrexate is the gold standard and it works by inhibiting folate to stop cell division.

The biologics, like euthanercept, are amazing.

But they mop up TNF alpha and can open the door to serious infections like TB.

And the final takeaway, number five.

Gout is a plumbing problem.

You either unclog the drain with probenacid, you turn off the faucet with allopurinol, or you bring in a powerful drain cleaner to dissolve the mess with paglotticase.

That's a great summary.

And a final thought for our listeners to chew on.

I think it's all about the balance between relief and biology.

Pharmacology, especially in these diseases, is the art of intervening in an incredibly complex system.

We use the NSAIDs to make the patient feel human again today, but we use the DMARDS to alter the destiny of their joints for tomorrow.

The real clinical skill lies in managing the toxicity of both at the same time.

Well said.

We really hope this last -minute lecture helps you crush that exam, go review those figures, memorize those key drug names, and we will see you on the next Deep Dive.

Good luck.

Goodbye.