Exam 3: Parkinsons Flashcards
PD Symptoms
TRAP
resting tremor (one side of body)
rigidity (muscle stiffness)
akinesia/bradykinesia (slow movement)
postural instability (impaired balance, coordination)
mask-like appearance
speech difficulties, cognitive deficits, depression
What is Parkinsons?
chronic, progressive, irreversible disease resulting from a neurological deficit in the extrapyramidal system
Pathophysiology of PD
gradual loss of darkly pigmented, dopamine-releasing neurons in the substantia nigra pars compacta in the midbrain
Dopaminergic neurons in the SNpc project to the ____ in the basal ganglia
striatum
PD involves a loss of neurotransmission through the _____________ system
nigrostriatal
______ of the nigral dopamine neurons or_________ of the nerve terminals in the striatum are lost before patients present with motor symptoms
50% ; 70-80%
Lewy Bodies
dense, spherical protein deposits in surviving neurons in the brain of PD patients
Where are Lewy Bodies found?
SN
Cortex
What are Lewy Bodies enriched with?
fibrillar forms of protein alpha-synuclein
Stage 1 of PD neuropathology
lower brainstem
Stage 3 of PD neuropathology
SN (necessary for classic PD symptoms)
Stage 6 of PD neuropathology
entire neocortex
SN pars compacta
undergoes neurodegeneration in PDWhat ma
What makes up the basal ganglia?
striatum (caudate nucleus, putamen) and globus pallidus
Dopamine Signaling Direct Pathway
a direct pathway involving D1 receptors i the striatum
simple
SNpc –> striatum –> Gpi/SNpr –> thalamus –> cortex
Dopamine Signaling Indirect Pathway
an indirect pathway involving D2 receptors in the striatum
(SNpc –> striatum –> Gpe –> STN –? Gpi/SNpr –> thalamus –> cortex)
complex
What signaling pathway is disrupted in PD?
signaling from the SNpc to both D1 and D2 receptors in the striatum favors thalmaocortical signaling
Use of antimuscarinics in PD
adjunct therapies for tremor in PD
Dosing of antimuscarinics in PD
used in low doses due to their side effects (cognitive deficits)
MOA of antimuscarinics
indirect pathway
loss of dopamine results in relative excess activity in cholinergic pathways
antimuscarinics curb this excess activity
Most effective treatments for PD
increase dopaminergic transmission by increasing endogenous dopamine or by directly stimulating dopamine receptors
Gold standard for PD therapy
L-dopa
Why can L-DOPA enter the CNS in contrast to dopamine?
Dopamine has a net positive charge at pH 7
What side effects can occur at high doses of L-DOPA?
nausea, hypertension, psychosis
The dose of L-DOPA can be lowered by ______ by co-administration of _________
Carbidopa
peripherally acting DOPA dexarboxylase inhibitor
allows L-DOPA to convert to dopamine only in the SN
Does carbidopa penetrate the BBB?
no
Challenges with L-DOPA therapy: oscillations
immediately after dosage, drug can produce dyskinesias
after plasma levels decline, drug may fail to provide any effect
Overcoming challenges with L-DOPA therapy: oscillations
problem can be alleviated by administering L-DOPA in a continuous manner
Challenges with L-DOPA therapy: prodrug conversion
L-DOPA must converted to dopamine by DOPA decarboxylase in surviving nigral dopaminergic neurons
as the disease progresses, patients become unresponsive to L-DOPA
Overcoming challenges with L-DOPA therapy: prodrug conversion
use a dopamine receptor agonist
postsynaptic dopamine receptors are still present in the striatum
Apomorphine MOA
mixed D1/D2 receptor agonist
administered subq in late-stage PD to provide rapid relief of the off-state
Apomorphine AEs
potent emetic effects
Non-ergolines
ropinirole
pramipexole
rotigotine
Non-ergolines MOA
D2/D3 agonists with fewer side effects than ergolines
generally used as monotherapies for early-stage PD, efficacy may last from 2-4 years
alternative to LDOPA
rotigotine dosage form
transdermal patch
MAO-B inhibitors
selegiline
rasagiline
MAO-B MOA
irreversible inhibitors of dopamine metabolism (=-)
inhibit the oxidation of dopamine to DOPAL
used to lower L-DOPA dose
Safinamide MOA
reversible MAO-B inhibitor (no =- group)
drug used as an adjunct to L-DOPA/cabidopa
COMT inhibitors
entacapone
tolcapone
COMT inhibitor MOA
inhibit the methylation of the 3-OH gropu of DA or L-DOPA by COMT
decreases the metabolism of L-DOPA in the periphery, allowing more to reach the brain (entacapone)
inhibition of COMT in the CNS by tolcapone allows levels of CNS dopamine to be higher
Nonmotor Symptoms of PD
anxiety
depression
constipation
dementia
insomnia
orthostatic hypertension
psychosis/delirium
sexual dysfunction
Non-pharm Therapy
important early on in disease
exercise/physical therapy
nutritional counseling
occupational therapy
psychotherapy/support groups
speech therapy
First Line Initial Treatment
rule out drug induced PD
dopamine precursor
dopamine agonist
MAO-B inhibitor
2nd Line Treatment
COMT
Amantadine
When to use Dopamine agonist as initial treatment
if age < 60 and higher risk for dyskinesia
avoid dopamine agonist as initial treatment if
age > 70
those with history of ICD
cognitive impairment
excessive daytime sleepiness
hallucinations
In general, initiate with IR _____ CR
>
In general, initiate with ________ effective dose to delay adverse effects or dyskinesias
lowest
Efficacy with motor symptoms
Levo/Carbi > DA > MAOB-I
Dopamine Precursors Place in Therapy
Levodopa/Cabidopa
first line therapy for initial PD
most effective monotherapy for motor symptoms
adjunctive therapy with dopamine agonists and other agents
Side Effects: Dopamine precursors
n/v
LD motor fluctuations/dyskinesias
hallucinations
Clinical Pearls: Dopamine precursors
starting dose: 25/100 mg CD/LD PO BID-TID with meals (up to 5-6x day)
titrate dose to balance efficacy and side effects
LD Motor Fluctuations: Wearing Off
before next dosing interval
signs and symptoms of motor symptoms
- increase CD/LD dose or frequency
- Add DA agonist, MAOI, COMTi
- XR CD/LD
LD Motor Fluctuations: freezing
inability to move due to insufficient or fluctuating DA levels
- increase CD/LD dose or frequency
- Add DA agonist (apomorphine)
- Add ODT CD/LD
LD Motor Fluctuations: delayed onset
therapeutic benefits delayed
- take CD/LD on empty stomach
- ODT CD/LD
- Avoid CR/XR CD/LD
LD Motor Fluctuations: peak dose dyskinesias
involuntary body movement caused by high DA levels
- decrease dose of DA or CD/LD
- add amantadine
Non-ergot Agonists Place in Therapy
Pramipexole, ropinirole, rotigotine, apomorphine
DA agonists first line for initial PD therapy
minimize LD motor fluctuations
Side Effects: Ergos/Non ergos
N/V
Sudden onset sleep
impulse control disorder
costs a lot of money
Starting dose: Pramipexole
IR : 0.125 mg PO TID
ER: 0.375 mg PO daily
Starting Dose: ropinirole
IR: 0.25 mg PO TID
ER: 2 mg PO daily
Starting Dose: rotigotine
2 mg patch q24h
Starting Dose: apomorphine
2 mg SC injection prn up to 5x daily
10 mg SL film up to 5x daily
Advantages of Dopamine agonists
fewer motor fluctuations
long acting formulations
Ergo place in therapy
bromcriptine, cabergoline
ergots used rarely due to toxicity
MAO-B inhibitors place in therapy
rasagiline, selegiline, safinamide
first line for mild symptoms
second line for adjunctive therapy
manage LD motor fluctuations
adjunctive for PD depression
Side Effects: MAO-B inhibitors
n/v
headach
insomnia (selegiline)
hypo/pertension
Starting Dose: rasagiline
0.5 mg po daily
starting dose: selegiline
5 mg po bid
starting dose: safinamide
50 mg po daily
Clinical Pearls: MAO-BIs
risk of serotonin syndrome with drug-drug interactions
dextromethorphan
serotenergic antidepressants
serotonergic opioidsC
COMT Inhibitors Place in Therapy
entacapone, opicapone, tolcapone
in combo to manage symptoms fluctuation (wearing off)
Side Effects: COMT inhibitors
N/V
brown/orange urine discoloration (entacapone)
heptotoxicity (tolcapone)
Starting Dose: entacapone
200 mg PO with each CD/LD dose
Starting Dose: tolcapone
100 mg PO TID
Starting Dose: opicapone
50 mg po QHS
Clinical Pearl: COMT Inhibitor
in early PD, no benefit of COMT inhibitors with CD/LD compared to CD/LD alone
Amantadine Place in Therapy
Management of LD motor fluctuations
modest effect in controlling motor symptoms, but rarely used monotherapy
Amantadine Side Effects
insomnia
confusion/hallucinations
livedo reticularis
Amantadine Clinical Pearls
usually reserved CD/LD peak dose dyskinesias
Starting Dose Amantadine
100 mg po BID
Anticholinergics Place in Therapy
management of tremor-dominant symptom in patients < 65 years old
benztropine, trihexyphenidyl
use limited by confusion and anti-muscarinic side effects avoid if > 65 years old
Starting Dose: benztropine
0.5 mg po qhs
starting dose: trihexyphenidyl
1 mg po daily
Constipation
increase fluid intake, physical activity if able
stool softeners/laxatives or probiotics
Insomnia
avoid benzos (diazepam, lorazepam)
Orthostatic Hypotension
non pharm counseling
midodrine/droxidopa
Anxiety/Depression
SSRI/SNRI
Avoid: benzos
CBT
Dementia
donepezil, rivastigmine
avoid: anticholinergics/benzos/antihistamines/sedatives
psychosis/delirium
avoid: haloperidol, olanzapine, paliperidone, risperidone
redose PD doses
pimavanserin (antipsych for PD)
atypical antipsychs (clozapine, quetiapine)
