Chapter 37: Alzheimer’s Disease – Cognitive Drug Treatments

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Welcome to the Deep Dive.

Today we're really getting into the specifics of pharmacotherapeutics for Alzheimer's disease, AED.

It's, well, it's the most common cause of dementia.

We know that, maybe 60 to 80 percent of cases, and it's characterized by that slow progressive cognitive decline.

The impact is just huge.

I think 5 .8 million people in the U .S.

alone costs in the hundreds of billions annually, and that doesn't even touch the unpaid care aspect.

It's a lot.

It really is.

And our goal today is to extract the key pharmacologic principles for managing the symptoms.

We're focusing on mechanisms, indications, clinical pearls, you know, straight from the advanced practice literature.

Think of it as a quick but solid review for clinical students.

Okay.

And we need to be upfront.

AD is currently incurable.

That's right.

It's a fatal disease.

The average lifespan after diagnosis is maybe four to eight years.

But, and this is the key point for today, the drugs we do have can offer temporary symptom improvement and, importantly, slow down that progression somewhat.

All right.

So let's build from the ground up.

The why behind the drugs.

We know about the hallmarks, the neurofibrillary tangles from tau protein, and those amyloid plaques.

The BAP plaques from abnormal ATP proteolysis.

So those structural changes,

they directly mess with neurotransmitters, right?

Two main systems.

Exactly.

That cell damage leads right to impaired neurotransmitter function.

First, you get destruction of cholinergic neurons.

Meaning less acetylcholine, which is crucial for learning memory.

Precisely.

Learning and memory.

That's target number one.

The cholinergic loss.

And number two.

That's the glutamatergic system.

Here, it's kind of the opposite problem.

You get excessive glutamate release, which overstimulates NMDA receptors.

Leading to, like, neuronal burnout.

Sort of.

It causes excitotoxicity, neuronal damage, and ultimately contributes to more cell death.

So you have this dual problem.

Not enough acetylcholine and way too much glutamate activity.

Okay.

That sets up the drug classes nicely.

Before we even think about prescribing diagnosis, how firm does that need to be?

And what else absolutely must be done first?

Good question.

The clinical diagnosis uses DSM -5 criteria.

But remember, definitive diagnosis is still only possible via autopsy.

Right.

So clinically, what's essential is baseline cognitive testing.

An MMSC, a MOCA.

You need that baseline to track response to therapy later.

And

crucially, rule out reversible causes of dementia first.

Box 37 .2 in the text highlights this well.

Think about medications the patient might be on anticholinergics, benzos, even H2 blockers can impair cognition.

And don't forget metabolic issues.

B12 deficiency, thyroid problems, hypo or hyper.

You absolutely have to check for and fix these mimics before labeling it AD and starting AD specific drugs.

That is such a critical clinical pearl.

Okay, let's jump into that first line of tackling the acetylcholine deficit,

the cholinesterase inhibitors, or CIs.

You've got Dumpezol, rivestigmine, galantamine.

Yep.

Their basic mechanism is pretty straightforward.

They inhibit the enzymes that break down acetylcholine, primarily acetylcholinesterase, which gives us the central effect we want.

But there's another one they hit too.

Right.

They also inhibit butylcholinesterase.

And that enzyme is more peripheral.

And inhibiting it is often linked to more of the unwanted side effects.

Ah, so that's the connection to things like nausea and diarrhea, the peripheral inhibition.

Exactly.

That's a big part of it.

Okay.

Are there key differences between these three CIs we should know?

There are.

Dumpezol is probably the most widely used, indicated for mild, moderate, and severe AD.

Easy, once daily dosing often makes it a first choice.

Okay.

Galantamine has a kind of interesting extra action besides inhibiting cholinesterase.

It also modulates the nicotinic receptor allosterically.

But rivestigmine is the most distinct.

The oral form has a unique dual indication.

Mild to moderate AD.

Yes.

But also mild to moderate dementia associated with Parkinson's disease.

Oh, interesting.

And then there's the rivestigmine patch.

That one is approved for mild, moderate, and severe AD.

And the patch formulation really helps lessen those intense GI side effects you can get with the oral form.

And you mentioned rivestigmine is pseudo -irreversible.

Yeah.

It binds for about 10 hours, so it's considered intermediate acting.

Not quite like the others.

Let's talk efficacy.

We know it's not a cure.

So what's the realistic benefit families should expect?

It's modest, but it's definitely there.

Compared to placebo, CIs generally slow down the cognitive decline by about six months.

Okay.

Six months delay.

Right.

They don't alter the underlying disease course.

But critically, they can also help with non -cognitive symptoms.

Things like apathy,

anxiety, agitation.

And reducing those can make a huge difference in quality of life and caregiver stress.

Now, for practical application dosing, this seems really important, especially titration.

You mentioned slow escalation for dunpeazle and the rivestigmine patch.

Why is that so critical?

It all comes back to those dose -dependent GI side effects.

Nausea, vomiting, diarrhea.

They hit harder at higher doses, especially initially.

You need to ease into it.

Absolutely.

With dunpeazle, you start at five milligrams daily.

You wait a good four to six weeks, see how the patient tolerates it, then consider increasing to 10 milligrams.

There's even a 23 milligram dose, but that's only for moderate to severe patients already stable on 10 milligrams for at least three months.

And the rivestigmine patch?

Similar idea.

Similar principle, different schedule.

You start at the 4 .6 milligram 24 -hour patch, then titrate up, usually at a 9 .5, then maybe 13 .3.

But you need at least four weeks between each dose increase.

Start low, go slow.

That's the mantra.

Oral rivestigmine, by the way, have the highest rates of those GI issues, sometimes up to nearly 50%.

Wow.

Okay.

Beyond the GI tract, any other serious adverse effects to watch for with CIs?

Yes.

Cardiac effects are a concern.

Because they increase cholinergic tone, they can cause bradycardia.

So you need caution in patients with things like six sinus syndrome or other underlying heart problems.

Also, they can increase gastric acid secretion.

So if a patient has a history of septic ulcer disease or is taking NSAIDs regularly, there's an increased risk.

Need to be mindful of that.

And the big interaction, the one that basically cancels out the drug's benefit?

Anti -cholinergics.

You absolutely cannot give a CI with an anti -cholinergic agent like, say, defenhydramine for sleep or allergies.

They work in opposite directions.

The anti -cholinergic will negate the cognitive benefit you're trying to achieve with the CI.

Always, always do a med reconciliation.

Crucial point.

Okay.

Let's switch gears to the other main problem, that excessive glutamate activity.

This brings us to Mementine, brand name Namenda,

indicated for more severe stages.

That's right.

Mementine is approved for moderate to severe AD.

It works completely differently from the CIs.

It's an NMDA receptor antagonist.

We said too much glutamate is toxic, but some glutamate signaling is needed for normal learning.

How does Mementine walk that line?

It's actually quite elegant.

Mementine is what we call a use -dependent blocker.

It essentially blocks the receptor channel when there's that pathological constant low -level glutamate stimulation that causes toxicity.

But it allows the channel to open during the brief strong bursts of glutamate needed for physiologic activation, like during learning and memory formation.

So it kind of dampens the harmful background noise without silencing the important signals.

That's fascinating.

So it's filtering, not just blocking everything.

Exactly.

What are the key things to know about dosing Mementine?

Like the CIs, you titrate it up.

The immediate release starts at 5 mg daily and goes up weekly to a target of 10 mg twice daily.

The extended release starts at 7 mg daily and titrates weekly up to 28 mg daily.

Okay.

Any big adjustments needed?

Yes.

And this is really important.

Renal function.

Mementine is mostly cleared by the kidneys.

If a patient's creatinine clearance drops below 30 lm in, you must use a lower maximum dose.

That's a critical check.

Got it.

Renal dose adjustment for CRCL less than 30.

And it can be used with CIs.

Yes.

Very commonly.

It's often added to a CI for moderate to severe AD.

There's even a combination pill with Dunkezel and Mementine.

But that's typically only started once a patient is stable on Dunpezel 10 mg.

All right.

Let's put it all together.

The treatment strategy.

If you have a patient presenting, walk us through the general algorithm.

Sure.

For mild to moderate AD, the first line is a cholinesterase inhibitor.

Often Dunpezel is tried first just because of the easier dosing and generally better GI tolerance profile initially.

Makes sense.

If the AD progresses to moderate to severe,

then Mementine becomes a first line option, either by itself or more commonly added to the CI the patient is already on.

And if the first CI doesn't work or isn't tolerated?

Then trying a different CI is a reasonable second line approach before moving on or adding Mementine if they're still in the mild to moderate stage.

Okay.

Now shifting slightly, the non -cognitive symptoms.

Psychosis, agitation, depression.

These affect maybe half of patients and are often the toughest part for families.

When do we step in with meds for these?

It's a high bar.

Generally, only if the patient's behavior is causing harm to themselves or others or significant distress.

And you have to be extremely cautious.

Especially with antipsychotics.

Absolutely.

There's that black box warning.

Antipsychotics increase the risk of death when used for dementia related psychosis.

And specific ones like risperidone and olanzapine have been linked to increased stroke risk too.

So if you must use one.

Lowest effective dose for the shortest possible time.

And you have to reassess regularly, say every three to six months to see if you can taper it down or stop it.

What about benzodiazepines for anxiety or sudden agitation?

They have a place, but it's very limited.

Maybe for episodic agitation or acute anxiety.

If you use one, you'd prefer a shorter acting agent like lorazepam or maybe alprazolam.

But not for regular use.

Definitely not.

Routine use is strongly discouraged.

The risks in this population are just too high falls, sedation, confusion, delirium, even worsening the underlying AD symptoms.

They should be the exception.

A last resort for acute situations, not the rule.

And depression.

It's common, right?

Very common.

And it needs treatment.

Here, SSRIs are generally preferred.

Sertraline, citalopram are good examples.

They tend to be better tolerated and have fewer of those problematic

anticholinergic side effects compared to older antidepressants like TCAs.

You'd expect to see a response in about four to six weeks.

Okay.

Moving toward wrapping up.

Monitoring.

How do we track if these cognitive enhancers are actually working?

It's not just about the MMSE score going up a point, is it?

No, not at all.

While you do use objective measures like the MMSE or MOCA at follow -up appointments, typically every three to six months, the real measure of success is functional.

Meaning?

Meaning input from the family, from the caregivers is absolutely crucial.

How is the patient doing with their activities of daily living, bathing, dressing, eating, and their instrumental ADLs, managing finances, medications, cooking?

Is the drug helping them maintain independence longer?

That's the goal we're for.

And deciding when to stop if there's no benefit or side effects are bad.

Exactly.

Discontinuation is perfectly reasonable if there's a clear lack of efficacy or if the side effects are intolerable.

But there's a caveat.

Which is?

If you stop a CI and within, say, three to six weeks, the family reports a marked rapid decline in function, you should seriously consider restarting it.

It might mean the patient was actually deriving a benefit that wasn't obvious until the drug was withdrawn.

Interesting point.

Okay.

Some final practical pearls for administration.

Yeah.

A couple of quick ones.

Dunpeazle can sometimes cause insomnia or vivid nightmares.

If that happens, just switch the dose from bedtime to the morning.

Simple fix.

Good tip.

And ribastic main, especially the oral form, should always be taken with food.

Helps minimize those GI side effects we talked about.

And one more thing, vitamin E.

Ah, yes.

Vitamin E.

Yeah.

There's some evidence it might delay

outcomes by about seven months in patients with moderate AD.

It's an antioxidant.

Sounds potentially useful.

But there's a catch.

Big catch.

You have to be extremely cautious if the patient is also taking warfarin or has a vitamin K deficiency.

Vitamin E can increase bleeding risk.

So if you recommend it, you absolutely must counsel the patient and family to watch for and report any unusual bruising or bleeding immediately.

Okay.

That's a really important interaction to be aware of, especially with something over counter.

So recapping this deep dive,

we have two main cognitive drug classes.

The colonesterase inhibitors, dunpeazle, ravastigmine, galantamine, primarily for boosting acetylcholine used across all stages, and Mementime, the NMDA antagonist for tackling glutamate excitotoxicity, mainly in moderate to severe stages.

And the key clinical takeaway for both is often that slow, careful titration to manage side effects, especially the cholinergic ones in the CIs, and stepping back looking at the bigger picture.

While these drugs target specific neurotransmitters, they only offer modest temporary benefits.

The real challenge, the true complexity in managing AD, often lies in supporting the patient's functional status day to day and managing the immense burden on caregivers.

So non -pharmacologic support is key.

Absolutely essential.

Patient and family education, connecting them with resources like the Alzheimer's Association or the ADER Center, that's arguably the most important intervention we have.

That brings us to a final thought for you, our listeners.

Think about that case study mentioned, MW, with mild AD, also on warfarin.

Considering the vitamin E discussion and that bleeding wrist, how vital does that make holistic patient assessment?

Really digging into all medications, including OTCs and supplements, checking all comorbidities before starting any new therapy.

That level of vigilance is really the core of advanced practice nursing.

Thank you so much for joining us for this deep dive into Alzheimer's pharmacotherapeutics.

We hope this was helpful and we'll catch you on the next one.