Alzheimer's pharm 1/22 Flashcards
alzheimer’s path
from plaques containing beta-amyloid,tangles containing phosphorylated tau,cortical hippocampal atrophy
these can lead to destruction of cholinergic neurons in basal nucleus of meynert in basal forebrain which provides cholinergic innervation to cerebral cortex.See short-term memory in early stages
causes of alzheimer’s
not clear.oxidative stress,inflammation or failure to clear A-beta-amyloid
chronic NSAIDs can reduce risk
diagnostic tests
Pittsburgh imaging compound B (PIB) is a radioactive tracer which binds amyloid in brain and can be imaged using PET–>PIB-PET:aggregation process starts before symptoms
tau proteins
normally provide structural supports to neurons
in alzheimer’s,they become detached and clump in tangles
other diagnostic tests using tau proteins
measure tau proteins in CSF.Also look for decreasing level of beta amyloid which occurs as peptide removed from fluid to deposit in brain
increased tau and decreased beta-amyloid–>advanced disease
diagnostic and monitoring imaging
volumetric MRI=measures shrinkage of brain as neurons expire
fluorodeoxyglucose-PET(FDG-PET)=gauges metabolic status of neurons
mutations in amyloid precursor proteins (APP)
leads to formation of either A-beta amyloid in general or a particular type of A-beta that is highly prone to forming deposits
pts with down’s
higher incidence of Alzheimer’s at a younger age
3 copies of chromosome 21 instead of two.this chromosome contains APP
mutations in presenilin1 and 2
essential for the functioning of gamma-secretase
variant of apolipoprotein called E4
pts with this variant involved in lipid metabolism–>higher risk for atheresclerosis and alzheimer’s
other risk factors
obesity in mid-life,HTN,HC
potential Tx options
1) inhibitors of enzyme producing beta-amyloid:block action of gamma secretase resulting in reduced APP–>amyloid peptides
2) vaccines or Ab that clear beta-amyloid:severe side effects in human.Bapineuzimab currently investigated
3) beta-amyloid aggregation blockers
4) Anti-tau compounds:
5) Neuroprotective agents:Nerve Growth Factor (NGF)
current Tx against Alzheimer’s
modest effect
AChEI used to treat mild-moderate
NMDA antagonist for moderate-severe
tacrine
first centrally acting CEI
generally not used due to severe hepatotoxicity
donepezil
reversible CEI in CNS and periphery
long 1/2 life,dosed once daily
side effects:n/d,headache,insomnia,anorexia,pain,urinary incontinence
contra:arrhythmias,seizures,asthma,COPD
may accentuate effect of succs,CYP450
galantamine
may be for alzheimer’s with cerebrovascular component
CEI and positive allosteric modulator of nicotinic receptors
two actions work together to enhance activation of nicotinic receptors
same side effects as donepezil
rivastigmine
CEI and butyrylCEI in glia
when cortical neurons die,gliosis occur–>butyrylCEI is important
GI side effects more severe than others. Could reduce with a skin patch
memantine
NMDA receptor antagonist
amyloid plaques cause small continuous release of glutamate that is excitotoxic
drug only blocks open NMDA channels with low to moderate affinity.also fast on and off time.Not powerful to block all NMDA transmission
also used for huntington,AID dementia and vascular dementia
side effects of memantine
dizziness,confusion,headache,HTN,
raising urine pH will reduce elimination
don’t combine with other NMDA blockers like ketamine,amantadine,dextromethorphan
Also vit.E as antioxidant
Non-pharm approaches
exercise and CV health (metformin)
support caregiver
behavioral approaches like distraction or close-ended questions
environmental modification
developing and maintaining routines
sensory intervention:music,pet therapy
other behavioral changes of dementia
psychotic:hallucinations,delusions,delusional misidentification
non-psychotic:agitation,wandering,aggression
atypical antipsychotics
first line of therapy
once daily at night for sedation
Quetiapine is lease likely to increase symptoms in Parkinson’s
typical antipsychotics
haloperidol at low doses to manage acute agitation and delirium
anticonvulsants
when psychosis leads to aggressive behavior as second-line
valproic acid or carbamazepine
