parkinson's Flashcards
3 features of PD — pathophysiology
- Lewy bodies
- degeneration of dopaminergic neurons
- basal ganglia
lewy bodies
- Accumulation of aggresomes (aggregated proteins)
- Lewy bodies ~ deposits of a-synuclein and ubiquitin
- Eosinophilic cytoplasmic inclusions
- apoptosis
degeneration of dopaminergic neurons, substantia nigra
- Lewy body inclusion in substantia nigra
- Induce oxidative stress, nitric stress
- Molecular abnormalities
- Dysfunction of nigrostriatal pathway
- Loss of darked region
basal ganglia and motor control
- Affects motor control
- Involved in action selection
- Normally inhibit a number of motor systems
- Substantia nigra-mediated release of inhibition permits a motor system to become active
- Involves both excitatory D1 and inhibitory D2 receptors
- Loss of substantia nigra –> no release of inhibition –> hypokinetic state
- Strong connection to other areas
- Thalamus, motor cortex etc
indirect vs direct pathways (basal ganglia)
DIRECT: hypoactivation of excitatory D1 receptors
* Weaken striatal inhibition of Globus pallidus internal
* Va/VL thalamus excites more motor pathway
INDIRECT: hypoactivation of inhibitory D2 receptors
* Strengthen striatal inhibition of GPe (external)
neurotransmitter deficiency – PD
- Striatal dopaminergic deficiency
* Extrapyramidal motor sx (tremor, rigidity, bradykinesia) - Other neurotransmitters involved
* Non-motor sx
* Autonomic, psychiatric, sensory, ocular, gait imbalance
cardinal features of PD
- Tremor at rest
- Bradykinesia (slowness of movement)
* micrographia (smaller handwriting) - Rigidity (cogwheeling)
postural instability and gait disturbances
* stooped posture, reduced arm swing, masked facial expression
progressives features of PD
- Early yrs of disease: Rate of disability progression marked
- 10-15yrs after onset: Sig disability
- Later stage: pt more dependent in their activities of daily living
initial presentation
- Asymmetric
- +ve response to levodopa/ apomorphine (DA agonists)
- NOT PRESENT: Postural instability (& falls)
- NOT PRESENT: Autonomic dysfunction
- Less rapid progression
- Impaired olfaction ?
Can conduct neuroimaging
progressed disease
- Unable to perform basic ADLs (or cannot perform safely)
○ Mobility (walk, use stairs)
○ Feeding self
○ Grooming, personal hygiene
○ Toileting
○ Showering/ bathing
○ Continence (bowel, bladder) - Choking
- Pneumonia (from aspiration into lungs)
- Falls (mobility deficit)
progressive sx of PD
- Motor sx: fluctuations, dyskinesias
- Non-motor sx (fall, postural instability, postural hypotension, confusion, dementia - PDD, suboptimal nutrition, speech, sleep d/o)
- PDD: Parkinson’s Disease Dementia
PD timeline
- 20 yr prodrome
* hyposmia, constipation, bladder disorder
* sleep d/o, obesity, dep - clinical onset
* unilateral: tremor, rigidity, akinesia - II: bilateral disease
- III: poor balance
- IV: falls, dependency, cognitive decline
- V: chair/ bed bound, dementia (PDD)
measurement of disease progression
- Hoehn and Yahr staging
* prodrome –> I,II,III,IV,V (across 20 yrs) - MDS: Unified Parkinson’s Disease Rating Scale (UPDRS)
* research tool
* intellect, Activities of daily living, motor exam, complication of therapy (dyskinesia)
dx of PD
- Based on clinical sigs, physical examination, hx taking = 2/3 cardinal signs present
- Tremor
○ Resting, disappears with movement,, incr with stress - Rigidity
○ Cogwheel rigidity, leadpipe rigidity - Bradykinesia
○ Weakness, loss of dexterity, loss of facial exp, difficulty getting out of bed/chair, turning (walking), reduced blinking
- Tremor
overall parkinson tx strategies
- incr central DOPA/ dopaminergic transmission (levodopa+DCI, DA)
* L-tyrosine —> L-dopa (pass through BBB)
* L-dopa —-> dopamine (DOPA decarboxylase) - decr breakdown (COMTi, MAO-Bi)
* dopamine reuptake by presynaptic neuron
* enzymes: COMT, MAO-B - correct imbalances in other neurotransmitter pathways
* anticholinergics, NMDA antagonist (glutamate)
tx plan based on onset
- Early/ young onset PD = [Dopamine agonist] > levodopa (dyskinesia)
- Slower disease progression
- Features
○ < cognitive decline
○ Earlier motor complications
○ Dystonia (common initial presentation)
- Late -onset [poor levodopa response]
- Falls and freezing
- rapid course
goals of PD management
- Manage sx
- Maintain function & autonomy
No tx because PD is progressive, no neuroprotection available
levodopa MOA
Incr precursor to incr dopamine synthesis
L-dopa –> dopamine (DOPA decarboxylase, MAO, COMT)
concomitant with
- decarboxylase inhibitors: carbidopa/ benserazide
- Peripheral DCI (Prevent peripheral dopamine SE)
- Incr dopamine avail in central (convert to dopamine)
- incr F from 33% –> 75%
- not cross BBB
75-100mg OD
ratio of sinemet (carbidopa) , Madopar (benserazide)
DCI: LEVO
1 : 4 (Sinemet, Madopar)
1 : 10 (Sinemet)
indication for levodopa
- Gold standard – bradykinesia, rigidity
* less for speech, postural reflex, gait disturbances - Efficacious for sx management of early & late PD * but Low dose and Preferable to start at later stage
ADR of levodopa
- ST: NV, postural hypoTENsion, drowsy, hallucination, psychosis
- LT: motor fluctuations, dyskinesia (3-5yrs of initiate)
Irreversible
dyskinesia presentation + management
○ Involuntary, uncontrolled
○ Twitching, jerking
○ Peak dose dyskinesia (right after admin - due to lowered dyskineisa threshold)
* Reduce dose// use sustained release
○ Dystonia
- Management:
* amantadine
* replace specific dose w/ modified release levodopa
dyskinesia stage of levodopa
- stable phase
* motor function near normal (reach sx relief threshold)
* conc fluctuate w/o sx emergence - wearing off –> dyskinesia
* duration of motor response shortens
* sx appears b. doses (in morning) - peak dose dyskinesia
- on-off phenomenom
* severe fluctuations
* Appear at random but related to swings in drug conc
* Often and normal mobility difficult to achieve
manage wearing-off dyskinesia sx
- Sustained release forms
- Release levo/DCI over long period 4-6hrs
- Lower F (dose adj needed)
○ IR –> CR: incr dose 25-50%
○ CR –> IR: dose decr - Reduce morning stiffness (take last dose of day, pt can get through OM)
○ No crush, open capsule
DDI of levodopa
- Pyridoxine
- Cofactor for dopa decarboxylase
○ Take levo + DCI - HIGH DOSE: Vit B6 (haem issues)/ vit B complex tabs
- Cofactor for dopa decarboxylase
- Fe
- Decr absorption of levo (space out admin)
- Protein (food, protein powder)
- Decr absorption of levo (space out admin)
- Dopamine antagonists
- Metoclopramide, prochlorperazine
○ Switch to domperidone (antiemetic) - FGA
- SGA: risperidone
- Metoclopramide, prochlorperazine
- MAOi (within 14d) - incr NE = hypotensive