42 - PD patho Flashcards
PD
- ___ is a major risk factor (mean onset is 62.5 years)
- chronic, progressive, ___ , disease resulting from neurological deficit in the ___ system (noncortical voluntary motor control)
- age
- irreversible, extrapyramidal
PD symptoms (TRAP)
- Tremor - primarily ___
- Rigidity
- ___ (slow movement)
- Postural instability (impaired balance and coordination)
___ like appearance
speech difficulties, cognitive deficits, depression
unilateral
akinesia
mask
PD is characterized by a loss of ___ neurons in the ___
- loss of neurotransmission through the ___ system
some studies suggest that 50% of nigral dopamine neurons or 70-80% of the nerve terminals in the striatum are lost before patients present with motor symptoms
dopaminergic, substantia nigra pars compacta (SNpc)
- nigrostriatal
PD is also characterized by presence of ___ in various regions of the brain
- surviving neurons in the brains of PD patients have these dense spherical ___ deposits
- enriched with fibrillar forms of protein ___
Lewy bodies
- protein
- a-synuclein
a-synuclein neuropathology: Braak stages
data suggest that PD neuropathology starts in the ___ and progresses upward
stage 3: reaching ___ accounts for classic symptoms
progression in other stages likely accounts for ___ symptoms
brainstem
substantia nigra
non-motor
Midbrain
substantia nigra pc
- provides input to the basal ganglia, supplies ___ to striatum
- involved in ___ motor control and some cognition
- undergoes neurodegeneration in PD
dopamine
voluntary
dopamine neuron signaling pathways
direct: ___ receptors (simple)
- SNpc, striatum, Gpi/SNpr, thalamus, cortex
indirect: ___ receptors (complex)
- SNpc, striatum, Gpe, STN, Gpi/SNpr, thalamus, cortex
signaling from the SNpc to both D1 and D2 receptors in the striatum favors ___ signaling, and the effect is disrupted in PD
D1
D2
thalamocortical
antimuscarinics like ___ (Cogentin) are used as adjunct tharapies for ___ in PD
- only used in ___ doses (can cause cognitive deficits)
- ACh = ___ , dopamine = ___ (in the indirect pathway)
- loss of dopamine results in ___ of activity in cholinergic pathways
- most effective treatments increase ___ transmission by either increasing endogenous dopamine or by directly stimulating dopamine receptors
benztropine, tremor
- low
- excitatory, inhibitory
- excess
- dopaminergic
___ is the gold standard for PD therapy
- precursor of ___
- is orally active and can enter the CNS
- high doses cause ___ , HTN, and ___
- the dose can be lowered 4x by co-administration of ___ , a peripherally acting DOPA decarboxylase inhibitor
- combo drug: ___
L-DOPA
- dopamine
- nausea, psychosis
- carbidopa
- Sinemet
T or F: L-DOPA is orally active and can enter the CNS. There is a difference in bioavailability between L-DOPA and DA because DA has a net positive charge at pH 7
True
L-DOPA must be converted to dopamine in the ___, but not in the ___
- ___ inhibits DOPA decarboxylase (DDC) in the ___
- doesnt penetrate the ___ , and thus it cannot inhibit DDC in the SN
SN, periphery
carbidopa, periphery
BBB
challenges of L-DOPA
on/off ___ after several years of treatment
- immediately after dosage, exaggerated and aberrant motor effects known as ___ occur
- after plasma levels decline, the drug may fail to provide any effect ( ___ state)
- can be alleviated by administering L-DOPA in a ___ manner
oscillations
dyskinesias
off
continuous
challenges with L-DOPA
key limitation associated with ___ conversion:
- L-DOPA must be converted to dopamine by ___ in surviving nigral dopaminergic neurons
- patients eventually become unresponsive
- one way to address this challenge is to use dopamine receptor ___ . This is reasonable because the postsynaptic dopamine receptors are still present in the striatum
prodrug
- DOPA decarboxylase
- agonists
DA receptor agonist: apomorphine
apomorphine ( ___ ) is a mixed D1/D2 agonist
- in the apomorphine structure, you can see the structure of ___ held in rigid conformation
- drug administered subQ in ___ stage PD to provide ___ relief of the off state
- limited use due to potent ___ effects
Apokyn
- dopamine
- late, rapid
- emetic
DA receptor agonists: non-ergolines
3 drugs: ___ (Requip), ___ (Mirapex), ___ (Neuropro)
- D __ / D __ agonists with fewer SE than ergolines
- increase dose every 5-7 days (minimize SE)
- generally used as monotherapies for ___ stage PD (efficacy lasts for 2-4 years)
- ___ is delivered via a transdermal patch
ropinirole, pramipexole, rotigotine
- D2/D3
- early
- rotigotine
inhibitors of dopamine metabolism
MAO-B inhibitors: ___ (Deprenyl) and ___ (Azilect)
- both drugs are ___ , leads to ___ inhibition of MOA-B
- inhibit ___ of dopamine
- both drugs can be used initially as monotherapies to delay the first use of ___
- can also be used as adjuncts
triple bond
selegiline, rasagiline
- propargylamines, irreversible
- oxidation
- L-DOPA
inhibitors of dopamine metabolism
MAO-B inhibitor: ___ (Xadago)
- ___ inhibitor of MOA-B (no propargylamine group)
- used as an adjunct to L-DOPA/carbidopa (particularly useful during off episodes)
safinamide
- reversible
inhibitors of dopamine metabolism
COMT inhibitors: ___ (Comtan) , ___ (Tasmar), ___ (Ongentys)
- inhibit ___ of DA or L-DOPA by COMT
- ___ and ___ decrease the metabolism of L-DOPA in the ___ , allowing more to go to the brain
- ___ also allows levels of ___ dopamine to remain higher
- mixture of L-DOPA, carbidopa, and entacapone is called ___
entacapone, tolcapone, opicapone
- methylation
- entacapone, opicapone, periphery
- tolcapone, CNS
- Stalevo
