Exam 3 lecture 5 Flashcards
disease progression of PD
Develops over 5-10 years with an increase in motor symptoms.
Cognitive symptoms may be present after several years of PD
Life expectancy after diagnosis is 15 years
clinical presentation of PD (motor)
Tremor
bradykinesia
rigidity
parkinsonian gait (walking style)
Clinical presentation of PD (non motor)
Anxiety and depression
constipation
dementia
insomnia
Psychosis
non pcol tx of PD
Exercise/physical therapy
nutritional counseling
occupational therapy
psychotherapy
speech therapy
Pcol tx of pd
1st line- rule out drug induced PD
Dopamine precursor
dopamine agonist
MAO-B inhibitor
Rank drug efficacy with motor symptoms
Levodopa/carbidopa>DA>MAOB-I
for most PD pts we initiate
Levodopa
When to use dopamine agonist? WHen to avoid dopamine agonist?
Dopamine agonist may be used as initial tx if age<60 yrs and higher risk for dyskinesia
Avoid dopamine agonist as initial tx if
age>70
history of ICD
cognitive impairement
excessive daytime sleepiness
hallucinations
What is the dopamine precursor used in PD
CD/LD (carbidopa/levidopa)
place in therapy for PD for LD/CD
1st line for initial PD therapy
most effective monotherapy “gold standard”
side effects of LD/CD (!)
N/V
LD motor fluctuations/dyskinesia
hallucinations
starting dose of LD/CD (!)
25/100 mg CD/LD PO BID-TID with meals
What are LD motor fluctuations (!)
wearing off
Freezing
Delayed onset
peak dose dyskinesia
Define the LD motor fluctuations (!!)
wearing off- before next dosing interval, signs of motor symptoms
freezing- inability to move due to insufficient or fluctuating DA levels
Delayed onset- Therapeutic benefits delayed
Peak-dose dyskinesias- Involuntary body movement caused by high DA levels
What are the types of dopamine agonists used to treat PD
ergots and non ergots
Name none ergot dopamine agonists
pramiprexole
ropinirole
rotigotine
apomorphine
strating doses for non ergot dopamine agonists
pramipexole IR 0.125 mg PO TID; ER 0.375 mg PO daily
- ropinirole IR 0.25 mg PO TID; ER 2 mg PO daily
- rotigotine 2 mg patch applied to the skin Q24H
- apomorphine 2 mg SC injection prn up to 5 x daily or
10 mg SL Film up to 5 x daily
place in therapy for non ergot DA agonists? What is used more, ergots or non ergots? Why?
1st line for initial PD therapy
non ergots used more because they are less likely to cause LD motor fluctuations.
What are MAO-B i drugs? When are they used?
Rasagiline
Selegiline
Safinimide
less effective at controlling motor symotoms
place in therapy for MAO-B I drugs
1st line for mild symptoms of PD
2nd line for adjunct
starting doses of MAO-B I drugs
Rasagiline- 0.5 mg po
Selegiline- 5 mg PO BID
Safinamide- 50 mg PO QD
What drug drug i/a should we be aware of with MAO B i
serotonergic antidepressants
dextromethorphan
serotonergic opioids
COMT i MOA
Minimize breakdown of dopamine
COMT i drugs and place in therapt
entacapone
opicapone
tolcapone
in combo with levodopa/carbidopa. PRevents wearing offS
S/E of COMT i drugs
N/V
brown/orange urine discoloration for entacapone (!!!!!)
treatment initiation and flow for PD
Non pharm always first
DOPAMINE PRECURSOR (most)
(2nd line- DA, MAO-B, COMT)
MAO-B (contingent)
(2nd line- DA, dopamine precursor)
DA (contingent)
(2nd line MAO-B and COMT)
Pros, cons and who of dopamine agonists
pros- once daily dosing formulations
better tolerated by younger patients
limited by motor fluctuations
cons- expensive
less symptomatic benefits than CD/LD
many adverse effects
who- age <60 at higher risk of dyskinesia
Avoid dopamine agonists if
age>70
hallucinations
ICD
cognitive impairement
excessive daytime sleepiness
pros, cons, who of CD/LD
pros- gold standard due to symptomatic benefit
cheap
variety of dosage forms
cons- motor fluctuations
dosing frequency (can be >3x per day)
who- most
pros, cons, who of MAO-B
pros- generally well tolerated
delays onset of motor fluctuation
cons- least effective agent against motor symptoms
dietary restriction (risk serotonin syndrome)
who- high risk of motor fluctuations
minor sx
Develop a therapeutic plan to manage levodopa-induced
motor fluctuations (!!!) wearing off
wearing off- increase CD/LD doe or frequency
add DA agonist, MAOI or COMTI
XR CD/LD
Develop a therapeutic plan to manage levodopa-induced
motor fluctuations (!!!) freezing
increase CD/LD dose or frequency
add DA agonist
Add ODT CD/LD
Develop a therapeutic plan to manage levodopa-induced
motor fluctuations (!!!) delayed onset
Take CD/LD on empty stomach
ODT CD/LD
void CR/XR CD/LD
Develop a therapeutic plan to manage levodopa-induced
motor fluctuations (!!!) peak dose dyskineses
Add amantidine
lower dose of DA or CD/LD
Recommend management of non-motor symptoms for a
patient with PD (!!!)
constipation- evaluate for meds causing constipation
increase fluid intake, physical actvity
stool softener/ axatives or probiotics
Insomnia- melatonin
AVoid benzodiazepines (diazepam, lorazepam,
oxazepam)
orthostatic HTN- Non- pcol counseling
midrodrine, droxidopa
Medical equipment to stabilize it
Anxiety/depression- Avoid benzodiazepines,
CBT (cognitive behavioral therapy)
SSRI/SNRI
dementia- cholinesterase inhibitor (donepezil, rivastigamine)
avoid anticholinergics, benzodiazepines,
antihistamines, sedatives)
Psychosis/delirium- Avoid- haloperidol, olanzepine,
plaiperidone, risperidone
What are the cardinal signs of AD? Seen more in men or women?
brain shrinkage, senile plaques, neurofibrillary tangles
seen more in females
AD symptoms
memory loss (especially recent)
impaired ability to learn and reason
impaired ability to carry out daily activities, confusion and untidiness
anxiety, suspicion, hallucinations
motor dysfunction in later stages
environmental risk factors for AD
low educational level
reduced mental activity in late life
reduced physical activity in late life
head injury
neuropathology (loss of brain volume)
difference between amyloid plaques and neurofibrillary tangles
amyloid plaques- extracellular
neurofibrillary tangles- intracellular
amyloid plaques consist of amyloid B peptide (AB)
neurofibrillary tangles consist of hyper phosphorylated tau
Neuropathology primarily affect areas of higher cognitive areas of higher cognitive function, what areas are these and what is affected? (AD)
entorhinal cortex- memory formation/consolidation)
Hippocampus- memory formation/consolidation
Basal forebrain- learning
neocortex- memory, learning cognition
T/F pathology is causing synaptic degeneration (AD)
true
What is synapse loss in AD mainly due to?
reduced levels of neurotransmitters, especially ach, but also serotonin, norepinephrine, dopamine
What happens to neurons in areas close to neurofibrillary tangles and amyloid plaques
destruction of synaose
Genetic evidence suggests which pathogenic molecule is key for AD (AB or TAU)
AB- amyloid plaques
TAU- neurofibrillary tangles
genetic evidence suggests AB
mutations in AB precursors are linked to early onset AD
APP gene is located in which chromosome? What can this lead to
located in chromosome 21 (same one linked to downs syndrome)
can lead to AD like symptoms in 4th decade of life in trisomy 21 pts
Aβ peptide is released from the transmembrane amyloid precursor protein (APP) by the activity of
β-secretase (BACE1) and γ-secretase.
What happens if APP is cleaved by alpha secretase in middle of AB segment instead of β-secretase (BACE1) and γ-secretase.
Cleavage of APP by α-secretase in the middle of the Aβ segment releases a
non-amyloidogenic (non-toxic) fragment
difference between Aβ42 and Aβ40
Aβ42 forms amyloid fibrils more readily than Aβ40.
How is Aβ42 formed more that Aβ40 and what are the effects of this
Mutations in the APP gene favor cleavage by β- or γ-secretase, resulting in the
production of more Aβ42 relative to Aβ40.
- Mutations in the gene encoding presenilin-1 or presenilin-2 (PSEN1 or
PSEN2), which are components of the γ-secretase complex, alter APP cleavage
by γ-secretase, resulting in the production of more Aβ42 compared to Aβ
What does AB aggregation lead to? (!!)
AB aggregation is thought to promote tau hyperphosphorylation leading to neurofibrillary tangle formation, cytoskeleton and disruption of axonal trafficking
why do anomalies with tau lead to disruption in cytoskeleton (!!)
Tau normal function is to be bound to microtubules and stabilize them. Anomalies affect this
In unhealthy areas where tangles have accumulated, the cytoskeletal
tracks are disrupted and disorganized, resulting in defects in axonal
transport that lead to synaptic dysfunction
effect of AB aggregation on microglial activation
AB induces neurotoxicity indirectly by triggering microglial activation.
what happens when microglia is activated by AB
Activated microglia release pro-inflammatory cytokines (e.g.
prostaglandins, interleukins, tumor necrosis factor-α) that cause neuroinflammation.
- Activated microglia also release reactive nitrogen species (e.g. nitric
oxide, peroxynitrite) and reactive oxygen species (superoxide,
hydrogen peroxide) that cause oxidative stress
Understand how ApoE genetics status modulates AD risk
There are three ApoE isoforms as a result of polymorphisms
in the ApoE gene: ApoE2, ApoE3, and ApoE4.
→ Individuals with one or two ApoE4 alleles have an increased
risk of AD, whereas inheritance of the ApoE2 allele
decreases AD risk
Cholinesterase inhibitor use and drugs
Used to treat AD
Donepezil (aricept)
Rivastigimine
Galantamine
MOA of donepezil, rivastigamine, galantamine
Donepezil- Specific reversible inhibitor of ach
rivastigamine- inhibits acetylcholinesterase and butyrylcholinesterase
galantamine- selective reversible inhibitor of achetylcholinesterase and enhances action of acetylcholine.
Use antiglutaminergic agents and drugs?
Use- AD therapy
Memantine- NMDA antagonist that blocks glutamatergic
neurotransmission via a noncompetitive mechanism, reduces excitotoxicity
what is glutamate
an excitatory neurotransmitter that is required for learning and memory
Describe pathogenic mechanisms being targeted in the
development of new AD therapies.
1) AB targetting
2) non amyloid therapy
AB therapy targets
AB- generation(b and gamma secretase inhibitors)
AB-aggregation- (inositol, polyphenols)
AB clearence- (AB antibody)
non amyloid targets
Tau-kinase inhibitors
glutamate mediated excitotoxicity
inflammation of oxidative stress
Understand how florbetapir (18F) and other imaging agents can be used to monitor amyloid formation in living individuals (what is florbetapir and how does it work)
18F is a radiolabled agent that binds B amyloid visualized by PET scanning
Know similarities and differences between AD and other dementias (DLB, FTDP)
name and describe non AD dementias
Non-AD dementias
Vascular dementia- impaired judgement or executive function is a more common initial symptom than the memory loss characteristic of AD. Occurs as a result of brain injury associated with stroke.
Dementia with lewy bodies (DLB)- Combination of cognitive and parkinsonian symptoms. Visual hallucinations are core diagnostic features.
Front temporal dementia (FTD)- disinhibited behavior, poor impulse control, antisocial behavior. Neuropathology is characterized by presence of tau accumulations.
