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Pharmacology of Alzheimer's Disease Cheat Sheet by

Pharmacology of Alzheimer's disease.


Dementia occurs in a cluster of diseases (mental decline)
It is a prominent part of Alzhei­mer's disease.
Symptoms: forget­ful­lness, memory loss, reduced reasoning, trouble paying attention, impaired judgement and problem solving, visual perception issues that aren't related to normal age-re­lated changes, changes in person­ality and behavior, any other changes that interfere with a person's normal daily functions.
Dementia gets progre­ssively worse.

Pathph­ysi­ology of Alzhei­mer’s Disease

Medica­tions to Treat Dementia Behaviors


Image Explained

There is an enlarged left ventricle, a thinner cortex, an atrophied hippoc­ampus, and atrophy all over.
The hippoc­ampus is respon­sible for spacial and recent memory. This is where Alzhei­mer's starts.

Cholin­est­erase Inhibitors

MOA: Prevents the breakdown of ACh, leading to increased ACh and increase in cholin­ergic activity in the CNS.
Indica­tions: better for mild cognitive impair­ment, you must have cholin­ergic neurons left. NO disease modifying effects seen
Side Effects: mainly GI related (N/V/D­/An­orexia, advise taking with food to help), could cause bradyc­ardia (risk of syncope, increased fall risk)
Contra­ind­ica­tions: Pregnancy, liver disease, peptic ulcer
Consid­era­tions: should be tapered off, otherwise can cause discon­tin­uation syndrome: difficulty concen­tra­ting, altered consci­ous­ness, delirium, halluc­ina­tions, insomnia, agitation, anxiety, labile mood
Rule of Thirds: 1/3 of patients will improve on these, 1/3 of patients will stabilize (slow progre­ssion tempor­arily), 1/3 of patients will experience no improv­ement.
Donepezil (Aricept): Oral tablet (Aricept), ODT (Aricept RDT), patch (Adlar­ity), ER caps combo with memantime for more severe cases (Namza­ric). Well tolerated and is NOT hepato­toxic T1/2 ~70 hours. Also approved for severe cognitive impair­ment. Has less GI effects compared to other agents (Rivas­tig­mine)
Galant­amine (Razad­yne): Tablet (Razad­yne), ER capsule (Razadyne ER), oral soultion
Rivast­igmine (Exelon): Capsule (Exelon) patch

Lewy Body vs Alzhei­mer’s


Used only for severe anxiety.


MOA: antagonist of 5HT1A receptor
Indica­tions: used for anxiety and mild/m­oderate agitation
Anxiolytic drug.
Well tolerated.
Limited data in dementia patients.
Has addictive potential.

Five Pathol­ogical Types of Dementia

Alzhei­mer's disease- the most common cause of dementia
Vascular dementia- this type of dementia is caused by damage to the vessels that supply blood to you brain. Is caused by athero­scl­erosis in the carotid arteries, and other arteries serving the brain.
Lewy body dementia- on its own or in Parkin­son's dementia
Fronto­tem­poral dementia- atrophy of neurons that die off in the fronto­tem­poral region.
Mixed dementia.

Pathop­hys­iology of Alzhei­mer's Disease

It is a progre­ssive memory impair­ment, dementia, and cognitive dysfun­ction.
It occurs in up to 20% of patients over 85 (5th leading cause of death 65+)
It is a progre­ssive loss of neurons, especially cholin­ergic neurons.
There is also an inflam­matory process.
There is increased amyloid beta peptide deposits in the cerebral cortex (they are insoluble so they stick together) this leads to plaque formation, lesion, and neuronal fibrillary tangles (Tau proteins)
The alpha and beta tubulin dimers are wrapped around in a spiral to hold the microt­ubule together. Normally the tau protein holds microt­ubules together. But the hyperp­hos­pho­ryl­ation of tau causes a disass­oci­ation of the microt­ubules, forming a "­clu­mp" that tangles.
Mitoch­ondrial dysfun­ction.
Increased glutamate activity may also play a role (NMDA receptor)
The bottom line is there is an increase in amyloid beta and a decrease in amyloid beta breakdown.
This typically starts out in the hippoc­ampus, it spreads out from there.
Found in 20% of patients over 85.

Alzhei­mer's Pharma­cology

Cholin­omi­metic drugs are a main focus of Alzhei­mer's therapy because there is evidence of loss of cholin­ergic neurons in this disease.
Decreasing glutamate is another focus of therapy due to excess glutamate excitation being present in this disease.

NMDA Receptor Blockers

Drug: Memantine (Namenda)
MOA: by blocking NMDA receptor, decreases the activity of glutamate
Place in Therapy: used in patients with more moderate cognitive impairment
Formul­ation: comes in a titration pak until goal dose achieved
Side Effects: overall well tolerated, more common ADRs are dizziness, confusion, HA, consti­pation.
Contra­ind­ica­tions: Gastric ulcers, lung disease, heart disease, kidney disease.
Consid­era­tions: Patients should taper off of memantine, Abrupt discon­tin­uation could lead to withdrawal effects like insomnia, aggres­sion, delusions, and disinh­ibi­tion. Treatment should be stopped after 6 months if no improv­ement is seen.
Other notes: has a long half life 60-80 hours, 100% absorbed orally. Memantine in combin­ation therapy with a cholin­est­erase inhibitor is recomm­ended in moderate to severe disease (efficacy not shown in mild disease) Memantine comes in combo with Donepezil (Namza­ric)**


Citalopram (has the most data), escita­lopram, sertra­line, mirtaz­apine, trazodone
citalo­pram, sertraline
Insomn­ia/­Sleep problems:
trazodone *antid­epr­essants haven't been studied for anxiety in dementia
Duloxe­tine, desven­laf­axine
citalo­pra­m/e­sci­tal­opram: QT prolon­gation, limit dosing
trazodone: sedation and orthos­tatic hypote­nsion risk
Avoid TCA due to antich­oli­nergic effects (already low on ACh)


MOA: blocks the NMDA receptor, reduces agitation, reduced excito­tox­icity in cholin­ergic nerves, inhibits the breakdown of dextro
Indica­tions: Used for agitation in Alzhei­mer's disease, FDA approved for pseudo­bulbar effects (uncon­trolled laughi­ng/­crying due to neurol­ogical condition)
Formul­ation: oral every expensive

Charac­ter­istics of Alzhei­mer's Disease

Memory Decline
They start having: learning problems, trouble with problem solving, poor judgement making, trouble commun­ica­ting, depression and mood swings
Sundowners syndrome- in the later aftern­oon­/early evening they experience additional confusion, irrita­blity, agitation, prancing, and wandering.
Finally there is a loss of self care.

Parkin­son's Disease with Lewy Body

Lewy body dementia are dementia with Lewy bodies and Parkin­son's disease dementia.
Lewy bodies are made up of brain proteins that are misfolded and forms aggreg­ates. The protein aggregates causes cell death.
This type of dementia is the 3rd most common type of dementia.
Quetiapine and Clozapine are used off-label. Can also use Achase inhibi­tors.
It is important to determine Lewy body vs. Alzhei­mer's because the pharma­cot­herapy is different.
Lewy Body vs. Alzhei­mer's: lewy body has reduces DA uptake vs Alzhei­mer's. Lewy body has less temporal lobe atrophy it can be confirmed on MRI. Lewy body has less occipital lobe glucose metabolism per PET scan. (this may be the reason for increased visual halluc­ina­tions in Lewy body because of occipital lobe hypome­tab­olism)

Alzhei­mer's Disease and Acetyl­choline

Acetyl­choline (ACh) is released by neurons in the CNS.
It is involved in memory, motiva­tion, arousal, and attention.
ACh is broken down by acetyl­cho­lin­est­erase.
In Alzhei­mer's disease, there is a decreased synthesis of ACh, which leads to impaired cholin­ergic function.
It begins in the hippoc­ampus and spreads out to all areas of the cerebrum.
1/3 of cases are inherited.

Monoclonal Antibody: Amyloid Beta

Monoclonal Antibody: Amyloid Beta

Aducanumab (Aduhelm)
MOA: a monoclonal antibody against amyloid beta plaque
Place in therapy: FDA approved for MILD cognitive impair­ment, approved with the accele­rated approval pathway (saw a plaque reduction but plaque reduction hasn't been associated with clinical improv­ements) cost is high, efficacy data is lacking, insurance doesn't like to cover it.
Formul­ation: given as a 1 hour infusion every 4 weeks
Side Effects: edema, cerebral microh­emo­rrhage -> patients must have MRI at start and contin­ually to monitor any changes.
Consid­era­tions: $56,000, serious side effects, benefits unknown. Has been shown to reduce plaques.


Psychosis: delusions, halluc­ina­tions, and paranoia
Only used in patients with severe agitation or psychosis that are distre­ssing to the patients or makes them act in a way that they are dangerous to themselves or others. This is a last resort.
They are not to be used as a chemical restraint
There are not a lot of benefit seen in these drugs in the popula­tions, LOTS of side effects. Most evidence with aripip­razole, olanza­pine, risper­idone. Halope­ridol is reserved for emergency use.
Caution: CV events, metabolic effects of antips­ych­otics (weight gain, DM, dyslip­ide­mia), sedation, QT prolon­gation
Labeled waring for antips­ychotic use in patients with dementia- increased risk of death and cerebr­ova­scular events

Cognitive impairment

Cholin­est­erase inhibitors will help attention, executive function (emotions, memory, impulse control, tasks, organi­zation) and visuos­patial deficits (spatial judgement, visual analysis)
Donepezil or Rivast­igmine recomm­ended as first line options.
Memantine NOT shown to work in this popula­tion.

Psycho­sis­/Be­hav­ioral Symptoms

Cholin­est­erase Inhibitors are shown to help with behavioral symptoms, there is limited evidence that they help with halluc­ina­tions and delusions. They can help with negative symptoms (things missing from person­ali­ty-­emo­tion, speech, motiva­tion, and anhedonia)
Last line: antips­ych­otics- unlikely effective and may worsen motor symptoms
Quetiapine or Clozapine may be tried at low doses, doesn't affect motor symptoms
Nuplazid (pimav­ans­erin): FDA approved for halluc­ina­tio­ns/­del­usions associated with Parkin­son's disease (positive diseases)
Positive symptoms are things that are there: halluc­ina­tions, delusions
It blocks the 5HT2A and C receptors, NOT DA receptors so less effects on motor symptoms. High risk of side effects or death (almost 10%). QT prolon­gation. Also helps with anxiety.


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