sessions 6/7: Alzheimer's Disease

galantamine chemistry

-CNS targeted -complex mechanism, maybe nonclassical bioisosteres (PAM of nAChRs) cyclic rings=complex mechanism

rivastigmine side effects

-GI (N/V/D)-give with food or use patch -headache, fatigue, insomnia

donepezil side effects

-GI (N/V/D/anorexia) *can give w food* -headache -patch: application site dermatitis

imaging alzheimer's

-MRI, CT (not diagnostic, but useful) -PET or SPECT to locate pathology

anti-amyloid monoclonal antibody

-aducanumab (Audhelm) -lecanemab (Lequembi)

medication issues

-age associated changes (renal, phase I metabolism) -polypharmacy -drug induced delirium -caution for all CNS drugs -increased risk for orthostasis and falls

behaviors in alzheimer's

-agitation -wandering -psychosis -depression *may need to use antipsychotics*

overall cholinesterase inhibitor therapeutics

-all equally efficacious (choose agent based on patient and provider preference) -lack or loss of efficacy or intolerability-->can switch bc only meant to help symptoms not modify disease

pathophysiology

-amyloid plaques -plaques form tangles

aducanumab and lecanumab MOA

-anti-amyloid monoclonal antibody -reduces amyloid plaques

moderate alzheimer's

-assistance w ADLs -disorientation to time/season -recall of recent events impaired -forgetful of family member names or recent events -daily function -denial -suspicious, tearful, agitated, paranoid -delusions

precautions w cholinesterase inhibitors

-asthma/COPD -cardiac conduction abnormalities (sick sinus syndrome)

diagnosis: MCI

-biomarker evidence of brain changes -subtle problems w memory and thinking

rivastigmine patch

-can be used for severe AD -daily patch

what is required for reversible inhibition of AChE

-carbamate (hard to remove) -quaternary nitrogen (anchors to enzyme site)

galantamine side effects

-cholinergic -GI (nause, vomiting) *give with food*

how to make clinical diagnosis

-complete medical history (family, social (substance abuse), psych) -physical exam -med history -other dx tests (LP, EEG, ECG) -alzheimer's criteria in DSM-5 historically confirmed by brain biopsy or autopsy, diagnosis of exclusion, usually complaint of caregiver

monitoring

-continuous assessment of cognition, physica;/functional status, mood/behavior -patient and caregiver interviews -documentation of specific behaviors -observation of SE, efficacy,m dose adjustments, status changes

reducing pathophysiologic risk

-deep sleep promotes prevention of plaque accumulation -AD is inflammatory (release of cytokines, NO, free radicals, complement resulting in injury and promoting inflammation) -possible use of NSAIDs

DUMBELLS (AE)

-diarrhea -urination -miosis -bradycardia -bronchoconstriction -emesis -lacrimation -lethargy -salivation -sweating

mild alzheimer's

-difficulty remembering events -intact IADLs -withdrawal from difficult tasks/hobbies -denial -get lost while driving

cholinesterase inhibitors

-donepezil (Aricept) -galantamine (Razadyne) -rivastigmine (Exelon)

glutamatergic neurotransmission

-glutamate released into synapse to act on ionotropic and metabotropic receptors -fast synaptic excitatory NT in CNS

glutamate and AD

-glutamate=excitatory and binds to NMDA causing influx of calcium and depolarization (Mg2+ blocks other receptors) in order to create memories and learning pathways -in AD: high glutamate keep calcium channels open-->hyperpolarization-->cell death (Mg2+ blocked from re-entering and blocking channel pore) prevent neurotoxicity by blocking NMDA receptor

neurofibrillary tangles (tau in dif words)

-healthy neurons: internal support structure made up of microtubules -tau binds to MT and stabilized them -AD: tau changed and tangles-->MT disintegrate and neuron dies

treatment goals for AD

-improve QoL -maximize functional performance -enhance cognitive ability -maintain independence as long as possible -lifestyle -treat underlying conditions -caregiver support and education -manage difficult behaviors

risk factors

-inc age -family hx (first degree relative) -risk genes (Apoe4) -head injury -vascular risk factors (high cholesterol, diabetes, hypertension)

memantine efficacy

-ineffective in mild -can improve cognitive function 12-24 weeks -can use as monotherapy or with cholinesterase inhibitor

memantine chemistry

-looks like amantadine reduces glutamate induced neurotoxicity

severe alzheimer's

-loss of ability to speak, walk, feed themselves -incontinence -requires 24/7 care

metabotropic Glu receptors

-mGlur1 and mGluR5: inc Ca2+ from sarcoplasmic reticulum through PLC pathway -others decrease cAMP

galantamine efficacy

-may improve cognitive function within 12-24 weeks -benefit can last up to 36 mos

rivastigmine efficacy

-may improve cognitive function within 12-24 weeks -benefit can last up to 36 mos

antioxidant therapy: vitamin E

-may reduce oxidative stress and free radical accumulation -risk: bleeding, falls, GI side effects, adverse CV outcome *not recommended*

diagnosis: preclinial

-measurable brain changes -asymptomatic -no criteria for use

NMDA antagonist

-memantine (Namenda)

signs of alzheimer's

-memory loss disrupting daily life -challenges in planning or problem solving -difficulty completing familiar tasks -confusion w time or place -trouble understanding visual images and spatial relationships -new problems w words in speaking and writing -misplacing things and losing ability to retrace steps -dec or poor judgement -withdrawal from work or social activities -changes in mood, personality, and behavior

memantine MOA

-noncompetitive NMDA receptor antagonist -binds to magnesium site and functions as receptor blocker under conditions of excessive stimulation -does not affect normal transmission

diagnosis: dementia

-noticeable memory, thinking, and behavioral symptoms -impaired daily function -evidence of disease-related brain changes

location compared to deficiency in neurotransmission

-nucleus basalis of Meynert: ACh -raphe nucleus: serotonin -locus coeruleus: catecholamines -substantia nigra: dopamine -cerebral cortex: somatostatin, GABA, excitatory amino acids (glutamate)

causes of unfavorable behavior in alzheimer's

-pain -constipation -hunger -depression -fear/anxiety -loss of sleep -infection (UTI) -medication ADR

rivastigmine chemistry

-peripheral activity -CNS activity -pseudoirreversible -has carbamate

apolipoprotein e

-risk gene -binds to tangles, potential to cause plaques -not diagnostic three alleles: e2 (dec risk), e3: most common, e4 (inc risk) *does not predict severity*

antioxidant therapy: ginkgo bilobba

-safe and well tolerated SE: GI, headache, allergy, anxiety DDI: bleeding risk w anticoags and antiplatelets; can interact w MAOis *not recommended*

SLUDGE (AE)

-salivation -lacrimation -urination -diaphoresis -GI upset -emesis

cholinesterase inhibitors how to start

-start early and continuously -start low and titrate slow

anti-inflammatory therapy

-suggest dec risk of AD in patients on long term anti-inflammatory therapy (no RCT>6 mos showing efficacy) *side effects limit use esp in this population-risk vs benefit*

memantine dosage forms

-tabs, XR caps, solution XR: can be sprinkled on applesauce solution: use dosing device provided; directly in mouth

brain atrophy

-terminal, parietal, frontal lobes -occipital, primary motor cortex, somatosensory unaffected

cognitive screening: MMSE

-test for orientation, registration (immediate memory), attention, and calculation, recall, language -estimates severity and progression of cognitive impairment -relies on verbal response, reading, writing, and hearing of patient

cholinergic hypothesis

-widespread cell degeneration results in NT deficits -need ACh for memory formation -loss of ACh correlated to severity of AD

ionotropic Glu receptors

1. AMPA 2. Kainic acid 3. NMDA

treatment recommendations: mild to moderate AD

1st line: cholinesterase inhibitor (titrate every 4 weeks to max tolerated dose) -if ineffective or not tolerated-->switch to another -still ineffective-->switch to memantine

treatment recommendations: moderate to severe AD

1st line: either cholinesterase inhibitor or memantine -if ineffective: combo therapy -loss of benefit or intolerance: switch cholinesterase inhibitor

donepezil dosing

23mg higher dose for severe but more side effects -patch kept in fridge *no renal or hepatic dose adjustments* -comes as tab, ODT, patch

non-pharm alzheimer's

5 R's -Reassess -Reconsider -Rechannel -Redirect/remove -Reassure

main deficiency in alzheimer's

Acetylcholine AChE target: donepezil, galantamine, rivastigmine

aducanumab and lecanumab dosing

IV infusions ada: every month lec: every 2 weeks

galantamine indication

MILD TO MODERATE

rivastigmine indication

MILD TO MODERATE

donepezil indication

MILD TO SEVERE

memantine indication

MODERATE TO SEVERE AD

aducanumab and lecanumab side effects

amyloid related imaging abnormalities (brain edema, microhemorrhages) *most minor but can be significant* ada: diarrhea, CNS: headache, falls, confusion, altered mental status *more CNS* lec: diarrhea, nausea, vomiting, hypersensitivity w infusion

plaques forming tangles

as the amount of tangles inc, so does the development of dementia and cell loss -cell loss can be due to impaired neuroplasticity and synaptic transmission through excitotoxicity, oxidative stress, and neuroinflammation

how is alzheimer's diagnosed?

based on clinical evaluation, no biomarkers

aducanumab and lecanumab monitoring

brain MRI ada: baseline, 7 mos, 12 mos lec: baseline, before 5th, 7th, 14th infusion

NMDA receptor

causes opening of Ca2+ channels, increases intracellular calcium in postsynaptic neurons, and with overstimulation leads to neurotoxicity via apoptosis

amyloid plaques

deposits of protein outside the neurons -consists of beta-amyloid, protein fragment snipped from a larger protein called amyloid precursor factor protein (APP) -fragments clump together and form dense, insoluble plaques -develop in areas of the brain used in thinking and decision making *unknown if precursor to AD or cause of AD*

memantine side effects

dizziness, confusion,m hallucinations, headache

galantamine MOA

enhances acetylcholine on nicotinic receptors in addition to cholinergic inhibition of AChE

what does adding a carbamate to AChE do?

enzyme workds at ester group and by adding carbamate (less electronegative) it is hard to remove and delays the amount of time it takes for AChE to break down ACh

early symptoms of alzheimer's

episodic memory loss, repeated questions, misplaced items, and appointments -most often noticed by family members and do not affect daily function

amyloid plaques

extracellular accumulations of AB, amyloid, B peptides formed by sequential cleavage of amyloid B-precursor protein by 2 enzymes

main excess in alzheimer's

glutamate -leads to neurotoxicity and cellular apoptosis drug: memantine

what does tau normally do?

helps stabilize microtubules in neurons

donepezil chemistry

high LogP (crosses BBB) -nonclassical bioisostere of AChE-->distance close to that of carbamates even though no carbamate present

tau

main precursor to neurofibrillary tangles in Alzheimer's disease is aggregated tau proteins

donepezil efficacy

may improve cognition, global functioning, behavioral symptoms within 12-24 weeks -benefit can last at least 2 years

aducanumab and lecanumab indication

mild cognitive impairment or mild dementia stage

cholinesterase inhibitor trial

minimum 6 months at optimal dosage (do not count titration time) -re-titration if interruption is >3 days -no washout period needed DO NOT USE MORE THAN ONE AT THE SAME TIME

alzheimer's disease

neurodegenerative disease associated with progressive impairment of memory and cognitive functions -can lead to completely vegetative state

alzheimer's onset

normally late, but is an autosomal dominant form of early onset AD

rivastigmine MOA

pseudo-irreversible inhibition of AChE and BChE

donepezil MOA

reversible and selective inhibitor of AChE

dementia

syndrome of impaired short and long term memory -compromised normal social or occupational function (ADL and IADL)

tau in alzheimer's

tau becomes hyperphosphorylated and fold abnormally, forming tangles inside neurons hyperphosphorylation: causes tau to detach from microtubules -tangles of tau disrupt transport system in neurons-->neuron death and can also form neuropil threads in dendrites and axons *accumulations of abnormal tau thought to begin ~10-20 years before sx of alzheimer's dementia become noticiable*

alzheimer's and death

usually complication of immobility such as pneumonia or PE, usually within 6-12 mos of original diagnosis

what do do if failure of all 3 cholinesterase inhibitors and memantine

withdraw therapy -6 month trial to assess efficacy -never use 2 cholinesterase inhibitors together