Chapter 18: Antidementia Drugs & Cognitive Disorders

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Welcome back to the Deep Dive.

Today, we are shifting gears a little bit.

We are usually into business trends or historical events, but today we are specifically tailoring this for our listeners who are right in the thick of it, our nursing students.

Yeah, that's right.

We've got a stack of notes, diagrams, and specifically chapter 18 of Psychiatric Nursing, seventh edition by Norman L.

Keltner.

That's right.

And you know, even if you aren't a nursing student, I'd say don't tune out.

This is a really fascinating look at how medical science tries to, well, treat the untreatable.

Right.

We are pulling apart the pharmacology of Alzheimer's disease, but our mission today is to translate this pretty heavy textbook chapter into what is essentially a masterclass audio lecture.

Yeah.

We want to clarify the concepts, the drug mechanisms, and the clinical considerations exactly as the text presents them.

But in a way that actually sticks in your brain.

Exactly.

In a way that you'll remember during an exam.

Exactly.

We're looking strictly at anti -dementia drugs.

And right away, looking at the notes from the author, Norman Keltner, he calls them Norm's Notes in the text, he sets the stage with a bit of a reality check.

A big reality check.

Yeah.

He basically says there isn't a whole lot society can do for a patient with Alzheimer's disease right now, but, and this is the key, understanding the mechanisms, the receptors, and the enzymes is critical.

It really is.

And that's the roadmap for this whole deep dive.

Keltner makes a really important point right at the start about the history of this field.

He says we have moved past the early days of psychopharmacology.

It used to be what he calls a serendipitous approach.

Serendipitous, meaning what, like lucky accidents?

Exactly.

Just we sort of stumbled upon drugs that worked.

We didn't know why they worked.

We just knew that they did something.

Right.

Throw it at the wall and see what sticks.

Pretty much.

But Keltner points out that now, even though we have serious limitations with Alzheimer's, the current approach is rational.

It targets specific physiologic mechanisms.

We aren't just guessing anymore.

We're targeting.

We're targeting.

So let's start where the chapter starts.

The drugs used for Alzheimer's disease, or AD, are put into two main buckets.

What are they?

So the text categorizes them as drugs used for treatment and drugs used for prevention.

Okay.

And Keltner is brutally honest right up front.

He provides that definitive cure that patients and families are so desperate for.

Of course.

But they can provide relief.

They might help prevent AD in some cases.

But as a nurse, you have to manage those expectations immediately.

Okay.

So before we even get to the drugs, let's unpack the disease itself because you can't really understand the treatment if you don't understand the damage, right?

Absolutely.

The text describes AD as degenerative, progressive, and brutal.

That's strong word for a textbook.

It is, but it's accurate.

I mean, it reflects the clinical reality.

The picture involved losing your memory making ability, aphasia.

Aphasia.

That's the word finding difficulty.

Yeah.

That frustrating inability to find the right words and then just generalize cognitive impairment.

But we really need to look at the neurobiology to understand the drugs.

The text points to two main causes for all this devastation.

Which are?

Neuronal death and neurotransmitter deficiency.

So on a structural level, the brain cells are literally dying.

Yes.

And on a chemical level, the messengers between them are drying up.

Precisely.

And right now, the most common treatment approach, it tries to restore that neurotransmitter loss.

There's a secondary approach that tries to actually halt the neurons from dying.

And we'll get to that later.

But the primary focus for the first part of this chapter is on restoring one specific

neurotransmitter, acetylcholine or H -hemp.

Right.

And the text mentions specific brain structures here that I think are important to visualize.

It says, neuronal loss happens everywhere, but the hippocampus is never spared.

Right.

And you have to think of the hippocampus as the factory where new memories are made.

The memory factory.

The memory factory.

If that factory shuts down, your ability to form new memories is gone.

You might remember 1975 perfectly, but you can't remember what you had for breakfast this morning.

And the text also highlights another structure, the amygdala.

Yes.

Which is located right in front of the hippocampus.

And this is fascinating.

The amygdala is the center of human emotion.

Keltner links this to how we select memories.

Right.

It's almost like a filing system based on feeling.

Yes.

That's a perfect way to put it.

The text explains that the amygdala plays a role in memorization selection.

Basically, we remember emotional events.

That's why you remember embarrassing moments or frightening moments so vividly.

The amygdala drives that.

It drives that selection.

But here is the key takeaway for the pathology.

The amygdala depends heavily on acetylcholine.

So as those ASHE pathways decline in Alzheimer's, that whole emotional memory function just suffers significantly.

Wow.

That really puts the symptoms in perspective.

It's not just forgetting keys.

It's a breakdown of the emotional machinery of memory.

It really is.

So if the problem is a lack of acetylcholine, the solution, logically, is to get more of it.

Let's move into that second section of the chapter,

restoring acetylcholine.

This is really the science backbone of the whole chapter.

To understand these drugs, you have to understand the cholinergic system.

The text notes that about 90 % of cholinergic fibers, these are the nerve fibers that use acetylcholine to talk to each other, they originate in a specific area.

Which is called?

The nucleus basalis of minute.

The nucleus basalis of minor.

Okay, that sounds like a location in a fantasy novel.

It does, doesn't it?

But in the context of AD, it's ground zero.

These specific pathways are selectively destroyed.

So you have a factory, the nucleus basalis, and it's shutting down.

Which means less acetylcholine is being shipped out.

Exactly.

Now the chapter uses a figure here, figure 18 to 1, to explain how acetylcholine is metabolized.

And this involves enzymes.

I think for a lot of students, the word enzyme just sounds

generic, biological magic dust.

But the text gives a very specific definition.

It does.

It defines enzymes as catalysts.

Keltner explains that an enzyme is a large molecule.

Other molecules, like neurotransmitters or drugs, they fit onto the enzyme like a key in a lock.

The enzyme changes them, it metabolizes them, but the enzyme itself isn't changed, it just repeats the action over and over again.

And the speed of this is just mind blowing.

The text gives a stat that I had to read twice.

A single enzyme molecule can metabolize how many acetylcholine molecules?

5 ,000.

Per second.

Per second.

Wow.

5 ,000 per second.

That is unbelievably fast.

It is.

So just imagine an acetylcholine estrous molecule, that's the enzyme, it grabs an acetylcholine molecule, snaps it into, breaks it down into inactive parts called choline acetate, and then it grabs the next one.

5 ,000 times.

Every second.

It's ferocious.

Ferocious efficiency.

So if you visualize the patient, they're already low on acetylcholine because the factory is shutting down.

And then waiting in the synapse, you have this Pac -Man enzyme eating up 5 ,000 molecules a second of the precious little acetylcholine that's left.

Exactly.

No wonder the brain is starving for a signal.

Right.

And that brings us to the core logic of the treatment.

If we want to restore acetylcholine, we can't just inject more of it.

It doesn't cross the blood -brain barrier well.

So you have to stop the destruction.

You have to stop the destruction.

You have to inhibit the enzyme.

If you block the acetylcholine estrase, you stop the breakdown.

That leaves more neurotransmitters available in the synapse to go and hit the receptors.

Speaking of receptors,

the text distinguishes between two types of receptors.

Muscarinic and nicotinic.

Why does a nursing student need to know the difference?

Is this just trivia or does it matter clinically?

Oh, it matters.

It matters a lot clinically.

It's all about the side effects.

Okay.

The text states that muscarinic receptors are the primary target for AD treatment.

But if you block these receptors, an anti -cholinergic effect, you get side effects that every nurse knows by heart.

The classic, can't see, can't pee, can't spit, can't, well, you know the rhyme.

That's the one, precisely.

Dry mouth, blurred vision, constipation, urinary hesitancy.

And the text makes a crucial nursing note here about those receptors.

It mentions drugs like diphenhydramine.

Benadryl.

Benadryl.

It blocks these muscarinic receptors.

Now, if you give benadryl to a healthy 20 -year -old for allergies, they get a little sleepy, a little dry mouth, no big deal.

But in an elderly person.

In an elderly person, blocking these receptors doesn't just dry out their mouth.

It can seriously compromise their cognition.

So you're saying giving benadryl to an Alzheimer's patient to help them sleep might actually make their confusion worse.

Yeah.

Because you're blocking the very system you're trying to save.

Exactly.

You are inducing a drug -related fog that mimics dementia.

The text says as people age, they become much more susceptible to these effects.

Oh, okay.

Now, on the flip side of the coin, you have the nicotinic receptors.

These are fascinating.

And these are the ones stimulated by nicotine from smoking.

Yes.

There are subtypes in the brain.

And when you activate these nicotinic receptors in the central nervous system, you get an upregulation of other neurotransmitters.

Like what?

Like norepinephrine, dopamine, and glutamate.

And all of this improves attention, memory, and mood.

Which leads to the smoking connection that's mentioned in the text.

This is surprising to me.

It is surprising, but it's biologically consistent.

The text points out that nicotine stimulates a specific receptor subtype called alpha -2.

This subtype has a big role in attention and memory.

So Keltner writes that this is why smoking can be putatively therapeutic in conditions like schizophrenia and ADHD.

Putatively therapeutic.

It's a very careful way of putting it.

It is.

We aren't telling you to smoke.

Exactly.

But the logic holds up.

Nicotine boosts attention in what's called sensory gating.

If you can't concentrate, you can't remember.

If you can't remember, you can't learn.

So strangely enough, the text suggests that targeting these nicotinic receptors is a potential avenue for cognitive improvement in the future.

Okay.

Before we get to the specific drugs, there's one more distinction in this science section.

We talked about the enzyme acetylcholinesterase, ACAE, but the text says there's another type called butyralcholinesterase, or BCEE.

What's the difference?

Location, location, location.

Acetylcholinesterase, ACAE, is common in the brain.

That is our target.

Okay.

Butyralcholinesterase, BCEE, is common in the periphery.

The gut, skeletal muscle,

the placenta.

So if a drug inhibits both of them, you're going to get side effects all over the body, not just in the brain.

Right.

If you inhibit BCEE in the gut and the muscles, that's where you get the nausea, the vomiting, the diarrhea, and the leg

So the text says the ideal drug would selectively inhibit ACAE in the brain and just leave BCEE alone to avoid all those nasty physical side effects.

That's the holy grail of selectivity.

Okay.

Quick recap.

We have the pathophysiology, neurons dying,

low acetylcholin.

We have the strategy, stop the enzyme from eating the acetylcholin.

Now let's look at the actual weapons, section three.

Colonist race inhibitors.

The text lists the big three.

Yep.

Dunpeazle, rivastigmine, and galantamine.

These are the workhorses.

They all work by attaching to that enzyme and preventing it from breaking down acetylcholine.

But before we get to those three,

the text takes a detour to discuss a drug called tacrine, brand name Cognex.

It says it's discontinued in the U .S.

Why spend time on a dead drug?

For the lesson it teaches, Keltner calls it a heuristic and ethical lesson.

Tacrine was the very first colonist race inhibitor.

Back in 1986, there was this huge article in the New England Journal of Medicine that claimed massive success.

What did it say?

It said one patient went back to work, another one took up golf again.

It was heralded as a miracle drug.

It was not even close.

The research was completely misrepresented.

The FDA actually issued an unprecedented rebuke to the authors for it.

Wow.

And tacrine failed for two reasons that are really important for students to understand.

One, it caused severe hepatotoxicity.

Liver damage.

Serious liver damage.

It just exhausted the liver's enzymatic resources.

And two, it wasn't selective at all.

It inhibited both ACE in the brain and BCE in the gut.

So patients had liver damage and terrible gastrointestinal side effects.

A terrible combination.

It was a mess.

So tacrine is out.

That brings us to Dunpeazle, brand name Aricept.

This was approved in 1996.

How is it different from tacrine?

Oh, it's a massive improvement.

First, it's much safer.

No hepatotoxicity.

So you don't need the constant liver function test that tacrine requires.

That's the big deal.

Huge deal.

Second, it has a long half -life, about 70 hours, which allows for once daily dosing.

That's huge for compliance, especially in elderly patients.

Sure.

And third, it is much, much more selective.

The tech says it is 1 ,200 times more selective for ACE in the brain than in the gut.

1 ,200 times more selective.

So theoretically, fewer stomach aches and leg cramps.

Theoretically.

But, you know, the techs notes that selectivity isn't perfect.

It still causes some GI issues.

And Brita Carney, that's a slow heart rate.

There's a specific box in the text, box 18 -2, that discusses a controversy about Dunpeazle dosing.

The standard dose was 10 milligram.

Then they released a 23 milligram version.

The tech seems skeptical.

Skeptical is the right word, yeah.

The text cites these two researchers, Schwartz and Miloshin, from 2012, and they ask,

why 23 milligram?

Right.

Why not 20 or 25?

Exactly.

Is the science really that precise?

The authors suggest it might be a patent extension strategy.

By creating a unique, weird dosage form, like 23 milligram, the manufacturer could keep the patent going for a few more years and delay the generics.

And Keltner seems to agree.

He says the cynicism has a ring of truth.

It's a great critical thinking point for students.

Just because a dose exists doesn't mean it's scientifically superior.

It might just be commercially superior.

Good point.

Okay.

Next up is Rivastigmine, brand name Exelon, approved in 2000.

What makes this one unique?

The mechanism of attachment is different.

Dunpeazle attaches to the enzyme, block of it, and then it slips off.

It's reversible.

Okay.

Rivastigmine is classified as irreversible or pseudo -irreversible.

It forms a covalent bond with the enzyme.

It's like superglue.

Essentially, yeah.

It doesn't just slip on and off.

It stays attached until the enzyme's life cycle is complete.

So even though it has a short plasma half -life of only about two hours, it's effective for 10 hours because it's physically stuck to the enzyme.

And the text also mentions a metabolic advantage for Rivastigmine, right?

Something about the liver.

Yes.

And this is huge for nurses who are managing polypharmacy.

Rivastigmine is not metabolized by the CYP450 system.

Meaning it has very few drug interactions compared to the others.

So if your

Rivastigmine plays nice with them.

But there's a downside.

The downside is it still causes peripheral issues.

You still get the nausea and vomiting.

That's actually why the patch form is so popular.

It bypasses the stomach.

Ah, that makes sense.

Okay.

Moving on to the third one.

Galantamine, brand name Razodine.

The text describes a dual mechanism here.

This is what really sets Galantamine apart.

Mechanism one, it inhibits the enzyme, just like the others.

But mechanism two is the kicker.

It stimulates presynaptic muscarinic receptors to release more acetylcholine.

Whoa.

So it stops the breakdown and encourages production.

In a way, yeah.

It increases the release.

It also modulates those nicotinic receptors we talked about earlier.

The ones related to smoking.

The very same.

And the text mentions that this might upregulate something called neurotrophic factors, like BCL2.

Neurotrophic factors.

That sounds like brain fertilizer.

That's a perfect analogy.

And because of this, the text suggests Galantamine might have a potential for neuroprotection, actually saving neurons from dying, which the others don't claim.

But it's a potential.

The big potential.

Keltner is careful to say this is if -replicable.

It's a potential advantage, not a guaranteed one.

So we have the big three.

Dunpeazle,

Rizostigmine, Galantamine.

What's the bottom line on how well they work?

If a nurse is talking to a family member who asks, will this fix my dad,

what should they say?

They need to be very, very honest.

The text summarizes it clearly.

These drugs do not slow the disease process.

Not at all.

They don't stop the neurodegeneration.

What they do is they mask the devastation.

They help the patient preserve their cognitive performance longer than if they hadn't taken the drug.

But if you stop the drug - They drop right back to where they would have been.

Exactly.

They drop to the cognitive level they would have reached anyway.

That is a sobering thought.

It's like propping up a collapsing building.

You aren't fixing the foundation.

You are just holding up the ceiling for a little while.

And eventually the text says, the underlying neurodegeneration becomes so profound that even these drugs can't mask it anymore.

The building just collapses.

Which leads us perfectly into section four.

We've talked about restoring acetylcholine.

Now let's talk about the other strategy.

Agents retarding neurodegeneration.

Stopping the actual death of the cells.

This shifts our focus completely.

We move away from acetylcholine and onto a different neurotransmitter.

Glutamate.

Glutamate.

The text calls it an excitatory neurotransmitter.

Right.

And usually excitation is good.

That's how we learn.

But in Alzheimer's, we have a problem called excitotoxicity.

Too much of a good thing.

Way too much of a good thing.

The mechanism involves something called the NMDA receptor.

That's N -Methyl -D -Aspiricate.

Normally, glutamate hits this receptor, a channel opens, and calcium flows in.

That calcium influx is the signal for learning and memory.

But in AD, there's a slow but steady leakage of glutamate.

Right.

So the channel stays open.

All the time.

It causes sustained depolarization.

The neuron is constantly firing, constantly on.

Too much calcium rushes in and that toxic overload kills the neuron from the inside.

It burns out.

That's excitotoxicity.

It's like the engine is redlining until it just explodes.

So enter Mementine, brand name Nemenda.

How does it stop this?

Mementine is an NMDA receptor antagonist.

It blocks the receptor.

But this is incredibly tricky.

If you block the receptor completely, you stop the excitotoxicity, yes, but you also stop learning.

You stop the good signal, too.

Right.

And the text makes a comparison to PCP -Fencyclidane here.

That was unexpected.

It's a vital comparison to understand the fine line that this drug has to walk.

PCP is also an NMDA antagonist.

But it blocks too much.

It blocks way too hard.

And that's why PCP users exhibit schizophrenia -like psychosis.

Exactly.

Their system is shut down too hard.

The text says Mementine has to be smart enough to distinguish between the background noise of the toxic leak and the strong signal of actual learning.

How on earth does it do that?

Figure 18 -3 uses magnesium to explain this.

Right.

So imagine the NMDA receptor is a doorway.

Normally, a magnesium molecule sits in the doorway acting as a bouncer.

It blocks calcium from getting in.

When a strong learning signal comes along, a big burst of glutamate comes and kicks the magnesium bouncer out of the way and the door opens for a second.

But in Alzheimer's, that bouncer is just getting overwhelmed.

The constant leak keeps the door ajar all the time.

So Mementine comes in and takes the place of the magnesium.

It sits in the channel, in the doorway.

It's strong enough to block the trickle of the toxic leak.

But, and this is the genius of the drug, when a strong intentional burst of glutamate comes along, a real memory signal, the Mementine moves aside.

So it blocks the noise but allows the signal.

Exactly.

It normalizes the intracellular calcium levels.

It prevents the death signal without preventing the learning signal.

It's really elegant.

And clinically, what are the logistics of Mementine?

How is it for patients?

It's generally well tolerated.

It has a long half -life, 60 to 80 hours.

And here is a key nursing point.

It is excreted, unchanged by the kidneys.

It is not metabolized by the liver.

So again, like Rivet -Stigman, fewer drug interactions.

Very few, which is great.

And unlike the cholinesterase inhibitors, which are mostly for mild to moderate AD, Mementine is often used for moderate to severe AD.

And they can be used together?

Yes.

The text mentions that combination therapy using Dumpizil and Mementine results in significantly slower rates of deterioration.

You're hitting the disease from both angles, boosting the signal with Dumpizil, and stopping the noise with Mementime.

That makes sense.

Okay, so that covers the approved drugs.

But the chapter also looks at the future and other pharmacologic approaches in Section 5.

What's on the horizon?

Two main categories here.

First, something called secretase inhibitors.

We know that in AD, these things called amyloid precursor proteins are snipped into pieces that then form plaques.

The plaques that gunk up the brain?

The very same.

And the scissors that do the snipping are enzymes called secretases.

So the theory is blunt the scissors.

Exactly.

Stop the snipping, stop the plaque.

The text says this is an evolving story.

It offers a lot of hope because it's getting at the core of the disease, trying to prevent the destruction.

But currently, the side effects are really serious, so it's not ready for primetime yet.

Okay.

And the second category involves drugs you'd usually find in a cardiac ward.

Dihydropyridine calcium channel blockers.

Things like amyloidapine or norvasc.

This is really interesting recent research that the text cites.

We know hypertension damages the blood -brain barrier.

And that damage might actually precede the cognitive decline.

These drugs block calcium channels to lower blood pressure, and that might also reduce amyloid formation.

There's a specific stat here that jumped out at me.

Yes.

It says that patients under the age of 75, taking these antihypertenses, decrease their probability of developing dementia by 8 % per year.

8 % per year?

That's pretty significant for a drug they might be taking anyway for their blood pressure.

It really is.

It connects the vascular health of the brain directly to the cognitive health of the brain.

It reinforces that old saying, what's good for the heart is often good for the head.

Okay.

Let's move to the last section, section six.

We've treated the disease, now can we prevent it?

The text lists several drugs to prevent Alzheimer's disease.

Yeah.

And the text is very cautious here.

It says the evidence varies, but because a lot of these drugs are generally benign, they might be worth promoting.

First up, NSAIDs.

So ibuprofen, naproxen.

What's the theory?

Inflammation.

The text refers to a low burner inflammatory process that slowly kills neurons.

The enzyme CAROX2 is the culprit here.

So the idea is that using NSAIDs to block CAROX2 might save neurons.

And does it work?

The evidence is tricky.

It suggests a decline in AD if NSAIDs are used for more than two years before symptoms start.

Before symptoms start.

That's the catch.

Once the disease passes a certain critical point, the text says NSAIDs are of no value.

It's purely a prevention strategy, not a treatment.

And of course, you have to weigh the risk of GI bleeds from long -term NSAID use.

Right.

Next up, statins.

Simple theory.

High cholesterol correlates with AD statins, lower cholesterol.

It's a logical leap.

You get dual benefits,

better heart health and potentially better brain health.

And then we have estrogen.

This feels like a bit of a myth -busting section in the text.

It absolutely is.

There was this long -held belief that because estrogen drops after menopause and AD risk goes up around the same time, giving estrogen would help protect the brain.

Seemed implausible.

It did.

But recent big studies have confirmed that estrogen does not reduce AD risk.

In fact, it actually increases cardiovascular risk.

So that is a dead end for AD prevention.

Okay.

Finally, vitamins.

B, D and E.

This ties back to an amino acid called homocysteine.

High levels of homocysteine are linked to AD.

B vitamins, B6, B12, folic acid, they all lower homocysteine.

So the logic suggests take B vitamins, lower your risk.

But there's always a but.

There's always a but.

The verdict in the text is no conclusive evidence.

It lowers homocysteine, sure, but we haven't actually proven it slows AD.

Same with vitamin E.

The text says recent evidence refutes its effectiveness.

What about vitamin D?

Vitamin D deficiency is definitely linked to cognitive dysfunction.

So keeping your levels up is a good idea for general health, but it's not a magic bullet for preventing Alzheimer's.

So we have a lot of maybe and you had to start 10 years ago strategies, but nothing definitive.

That is the reality of the field right now, unfortunately.

Before we wrap up, let's do the critical thinking review.

The text poses two specific questions for students.

Let's answer them based on what we've discussed.

Let's do it.

Okay, question one.

Why does a large dose of Benadryl cause fuzzy thinking in older adults?

Because Benadryl is a potent anti -cholinergic.

It blocks those muscarinic receptors we talked about.

And in an older adult whose cholinergic system is already fragile, that blockade cuts off the very neurotransmitter needed for clear cognition.

So you're creating a temporary drug induced dementia.

That's a perfect way to describe it.

Yes.

Okay, question two.

Should a friend diagnosed with AD start taking NSAIDs now?

Based on what the text says, the answer is likely no.

The benefit of NSAIDs appears to be in that prevention window at least two years before symptoms appear.

Once the diagnosis is made, the neurodegeneration is likely too advanced for the anti -inflammatory effect to reverse the course.

Okay, that brings us to the end of chapter 18.

What is the final takeaway for the nursing student listening to this deep dive?

I think the takeaway is about role clarity.

We are currently treating symptoms, not curing the disease.

The nurse's role isn't just about dispensing pills, it's about managing expectations.

Right.

It's monitoring for those side effects.

The bradycardia with Dunpeazle, the nausea with rivastigmine, the safety risks from confusion, and it's understanding that while we can't stop the storm, these drugs can provide a temporary shelter.

And understanding the mechanism, the why, helps you explain that to a frightened family.

Exactly.

That's where the compassion meets the science.

That's good nursing.

Thank you for joining us on this deep dive into psychiatric nursing.

We really hope this makes chapter 18 a little less daunting.

Keep studying, and we'll see you on the next one.

This has been the Last Minute Lecture Team, signing off.