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PHRM 845 > Exam 3: Parkinsons > Flashcards

Exam 3: Parkinsons Flashcards

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1
Q

PD Symptoms

A

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

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2
Q

What is Parkinsons?

A

chronic, progressive, irreversible disease resulting from a neurological deficit in the extrapyramidal system

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3
Q

Pathophysiology of PD

A

gradual loss of darkly pigmented, dopamine-releasing neurons in the substantia nigra pars compacta in the midbrain

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4
Q

Dopaminergic neurons in the SNpc project to the ____ in the basal ganglia

A

striatum

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5
Q

PD involves a loss of neurotransmission through the _____________ system

A

nigrostriatal

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6
Q

______ of the nigral dopamine neurons or_________ of the nerve terminals in the striatum are lost before patients present with motor symptoms

A

50% ; 70-80%

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7
Q

Lewy Bodies

A

dense, spherical protein deposits in surviving neurons in the brain of PD patients

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8
Q

Where are Lewy Bodies found?

A

SN
Cortex

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9
Q

What are Lewy Bodies enriched with?

A

fibrillar forms of protein alpha-synuclein

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10
Q

Stage 1 of PD neuropathology

A

lower brainstem

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11
Q

Stage 3 of PD neuropathology

A

SN (necessary for classic PD symptoms)

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12
Q

Stage 6 of PD neuropathology

A

entire neocortex

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13
Q

SN pars compacta

A

undergoes neurodegeneration in PDWhat ma

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14
Q

What makes up the basal ganglia?

A

striatum (caudate nucleus, putamen) and globus pallidus

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15
Q

Dopamine Signaling Direct Pathway

A

a direct pathway involving D1 receptors i the striatum

simple

SNpc –> striatum –> Gpi/SNpr –> thalamus –> cortex

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16
Q

Dopamine Signaling Indirect Pathway

A

an indirect pathway involving D2 receptors in the striatum

(SNpc –> striatum –> Gpe –> STN –? Gpi/SNpr –> thalamus –> cortex)

complex

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17
Q

What signaling pathway is disrupted in PD?

A

signaling from the SNpc to both D1 and D2 receptors in the striatum favors thalmaocortical signaling

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18
Q

Use of antimuscarinics in PD

A

adjunct therapies for tremor in PD

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19
Q

Dosing of antimuscarinics in PD

A

used in low doses due to their side effects (cognitive deficits)

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20
Q

MOA of antimuscarinics

A

indirect pathway

loss of dopamine results in relative excess activity in cholinergic pathways

antimuscarinics curb this excess activity

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21
Q

Most effective treatments for PD

A

increase dopaminergic transmission by increasing endogenous dopamine or by directly stimulating dopamine receptors

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22
Q

Gold standard for PD therapy

A

L-dopa

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23
Q

Why can L-DOPA enter the CNS in contrast to dopamine?

A

Dopamine has a net positive charge at pH 7

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24
Q

What side effects can occur at high doses of L-DOPA?

A

nausea, hypertension, psychosis

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25
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
26
Does carbidopa penetrate the BBB?
no
27
Challenges with L-DOPA therapy: oscillations
immediately after dosage, drug can produce dyskinesias after plasma levels decline, drug may fail to provide any effect
28
Overcoming challenges with L-DOPA therapy: oscillations
problem can be alleviated by administering L-DOPA in a continuous manner
29
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
30
Overcoming challenges with L-DOPA therapy: prodrug conversion
use a dopamine receptor agonist postsynaptic dopamine receptors are still present in the striatum
31
Apomorphine MOA
mixed D1/D2 receptor agonist administered subq in late-stage PD to provide rapid relief of the off-state
32
Apomorphine AEs
potent emetic effects
33
Non-ergolines
ropinirole pramipexole rotigotine
34
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
35
rotigotine dosage form
transdermal patch
36
MAO-B inhibitors
selegiline rasagiline
37
MAO-B MOA
irreversible inhibitors of dopamine metabolism (=-) inhibit the oxidation of dopamine to DOPAL used to lower L-DOPA dose
38
Safinamide MOA
reversible MAO-B inhibitor (no =- group) drug used as an adjunct to L-DOPA/cabidopa
39
COMT inhibitors
entacapone tolcapone
40
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
41
Nonmotor Symptoms of PD
anxiety depression constipation dementia insomnia orthostatic hypertension psychosis/delirium sexual dysfunction
42
Non-pharm Therapy
important early on in disease exercise/physical therapy nutritional counseling occupational therapy psychotherapy/support groups speech therapy
43
First Line Initial Treatment
rule out drug induced PD dopamine precursor dopamine agonist MAO-B inhibitor
44
2nd Line Treatment
COMT Amantadine
45
When to use Dopamine agonist as initial treatment
if age < 60 and higher risk for dyskinesia
46
avoid dopamine agonist as initial treatment if
age > 70 those with history of ICD cognitive impairment excessive daytime sleepiness hallucinations
47
In general, initiate with IR _____ CR
>
48
In general, initiate with ________ effective dose to delay adverse effects or dyskinesias
lowest
49
Efficacy with motor symptoms
Levo/Carbi > DA > MAOB-I
50
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
51
Side Effects: Dopamine precursors
n/v LD motor fluctuations/dyskinesias hallucinations
52
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
53
LD Motor Fluctuations: Wearing Off
before next dosing interval signs and symptoms of motor symptoms 1. increase CD/LD dose or frequency 2. Add DA agonist, MAOI, COMTi 3. XR CD/LD
54
LD Motor Fluctuations: freezing
inability to move due to insufficient or fluctuating DA levels 1. increase CD/LD dose or frequency 2. Add DA agonist (apomorphine) 3. Add ODT CD/LD
55
LD Motor Fluctuations: delayed onset
therapeutic benefits delayed 1. take CD/LD on empty stomach 2. ODT CD/LD 3. Avoid CR/XR CD/LD
56
LD Motor Fluctuations: peak dose dyskinesias
involuntary body movement caused by high DA levels 1. decrease dose of DA or CD/LD 2. add amantadine
57
Non-ergot Agonists Place in Therapy
Pramipexole, ropinirole, rotigotine, apomorphine DA agonists first line for initial PD therapy minimize LD motor fluctuations
58
Side Effects: Ergos/Non ergos
N/V Sudden onset sleep impulse control disorder costs a lot of money
59
Starting dose: Pramipexole
IR : 0.125 mg PO TID ER: 0.375 mg PO daily
60
Starting Dose: ropinirole
IR: 0.25 mg PO TID ER: 2 mg PO daily
61
Starting Dose: rotigotine
2 mg patch q24h
62
Starting Dose: apomorphine
2 mg SC injection prn up to 5x daily 10 mg SL film up to 5x daily
63
Advantages of Dopamine agonists
fewer motor fluctuations long acting formulations
64
Ergo place in therapy
bromcriptine, cabergoline ergots used rarely due to toxicity
65
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
66
Side Effects: MAO-B inhibitors
n/v headach insomnia (selegiline) hypo/pertension
67
Starting Dose: rasagiline
0.5 mg po daily
68
starting dose: selegiline
5 mg po bid
69
starting dose: safinamide
50 mg po daily
70
Clinical Pearls: MAO-BIs
risk of serotonin syndrome with drug-drug interactions dextromethorphan serotenergic antidepressants serotonergic opioidsC
71
COMT Inhibitors Place in Therapy
entacapone, opicapone, tolcapone in combo to manage symptoms fluctuation (wearing off)
72
Side Effects: COMT inhibitors
N/V brown/orange urine discoloration (entacapone) heptotoxicity (tolcapone)
73
Starting Dose: entacapone
200 mg PO with each CD/LD dose
74
Starting Dose: tolcapone
100 mg PO TID
75
Starting Dose: opicapone
50 mg po QHS
76
Clinical Pearl: COMT Inhibitor
in early PD, no benefit of COMT inhibitors with CD/LD compared to CD/LD alone
77
Amantadine Place in Therapy
Management of LD motor fluctuations modest effect in controlling motor symptoms, but rarely used monotherapy
78
Amantadine Side Effects
insomnia confusion/hallucinations livedo reticularis
79
Amantadine Clinical Pearls
usually reserved CD/LD peak dose dyskinesias
80
Starting Dose Amantadine
100 mg po BID
81
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
82
Starting Dose: benztropine
0.5 mg po qhs
83
starting dose: trihexyphenidyl
1 mg po daily
84
Constipation
increase fluid intake, physical activity if able stool softeners/laxatives or probiotics
85
Insomnia
avoid benzos (diazepam, lorazepam)
86
Orthostatic Hypotension
non pharm counseling midodrine/droxidopa
87
Anxiety/Depression
SSRI/SNRI Avoid: benzos CBT
88
Dementia
donepezil, rivastigmine avoid: anticholinergics/benzos/antihistamines/sedatives
89
psychosis/delirium
avoid: haloperidol, olanzapine, paliperidone, risperidone redose PD doses pimavanserin (antipsych for PD) atypical antipsychs (clozapine, quetiapine)

PHRM 845 (14 decks)

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