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PHRM 845 > Exam 3: Parkinsons > Flashcards

Exam 3: Parkinsons Flashcards

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
Q

The dose of L-DOPA can be lowered by ______ by co-administration of _________

A

Carbidopa

peripherally acting DOPA dexarboxylase inhibitor

allows L-DOPA to convert to dopamine only in the SN

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26
Q

Does carbidopa penetrate the BBB?

A

no

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27
Q

Challenges with L-DOPA therapy: oscillations

A

immediately after dosage, drug can produce dyskinesias

after plasma levels decline, drug may fail to provide any effect

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28
Q

Overcoming challenges with L-DOPA therapy: oscillations

A

problem can be alleviated by administering L-DOPA in a continuous manner

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29
Q

Challenges with L-DOPA therapy: prodrug conversion

A

L-DOPA must converted to dopamine by DOPA decarboxylase in surviving nigral dopaminergic neurons

as the disease progresses, patients become unresponsive to L-DOPA

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30
Q

Overcoming challenges with L-DOPA therapy: prodrug conversion

A

use a dopamine receptor agonist

postsynaptic dopamine receptors are still present in the striatum

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31
Q

Apomorphine MOA

A

mixed D1/D2 receptor agonist

administered subq in late-stage PD to provide rapid relief of the off-state

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32
Q

Apomorphine AEs

A

potent emetic effects

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33
Q

Non-ergolines

A

ropinirole
pramipexole
rotigotine

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34
Q

Non-ergolines MOA

A

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

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35
Q

rotigotine dosage form

A

transdermal patch

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36
Q

MAO-B inhibitors

A

selegiline
rasagiline

37
Q

MAO-B MOA

A

irreversible inhibitors of dopamine metabolism (=-)

inhibit the oxidation of dopamine to DOPAL

used to lower L-DOPA dose

38
Q

Safinamide MOA

A

reversible MAO-B inhibitor (no =- group)

drug used as an adjunct to L-DOPA/cabidopa

39
Q

COMT inhibitors

A

entacapone
tolcapone

40
Q

COMT inhibitor MOA

A

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
Q

Nonmotor Symptoms of PD

A

anxiety
depression
constipation
dementia
insomnia
orthostatic hypertension
psychosis/delirium
sexual dysfunction

42
Q

Non-pharm Therapy

A

important early on in disease

exercise/physical therapy

nutritional counseling

occupational therapy

psychotherapy/support groups

speech therapy

43
Q

First Line Initial Treatment

A

rule out drug induced PD

dopamine precursor

dopamine agonist

MAO-B inhibitor

44
Q

2nd Line Treatment

A

COMT
Amantadine

45
Q

When to use Dopamine agonist as initial treatment

A

if age < 60 and higher risk for dyskinesia

46
Q

avoid dopamine agonist as initial treatment if

A

age > 70
those with history of ICD
cognitive impairment
excessive daytime sleepiness
hallucinations

47
Q

In general, initiate with IR _____ CR

A

>

48
Q

In general, initiate with ________ effective dose to delay adverse effects or dyskinesias

A

lowest

49
Q

Efficacy with motor symptoms

A

Levo/Carbi > DA > MAOB-I

50
Q

Dopamine Precursors Place in Therapy

A

Levodopa/Cabidopa

first line therapy for initial PD

most effective monotherapy for motor symptoms

adjunctive therapy with dopamine agonists and other agents

51
Q

Side Effects: Dopamine precursors

A

n/v

LD motor fluctuations/dyskinesias

hallucinations

52
Q

Clinical Pearls: Dopamine precursors

A

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
Q

LD Motor Fluctuations: Wearing Off

A

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
Q

LD Motor Fluctuations: freezing

A

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
Q

LD Motor Fluctuations: delayed onset

A

therapeutic benefits delayed

  1. take CD/LD on empty stomach
  2. ODT CD/LD
  3. Avoid CR/XR CD/LD
56
Q

LD Motor Fluctuations: peak dose dyskinesias

A

involuntary body movement caused by high DA levels

  1. decrease dose of DA or CD/LD
  2. add amantadine
57
Q

Non-ergot Agonists Place in Therapy

A

Pramipexole, ropinirole, rotigotine, apomorphine

DA agonists first line for initial PD therapy

minimize LD motor fluctuations

58
Q

Side Effects: Ergos/Non ergos

A

N/V

Sudden onset sleep

impulse control disorder

costs a lot of money

59
Q

Starting dose: Pramipexole

A

IR : 0.125 mg PO TID

ER: 0.375 mg PO daily

60
Q

Starting Dose: ropinirole

A

IR: 0.25 mg PO TID

ER: 2 mg PO daily

61
Q

Starting Dose: rotigotine

A

2 mg patch q24h

62
Q

Starting Dose: apomorphine

A

2 mg SC injection prn up to 5x daily

10 mg SL film up to 5x daily

63
Q

Advantages of Dopamine agonists

A

fewer motor fluctuations
long acting formulations

64
Q

Ergo place in therapy

A

bromcriptine, cabergoline

ergots used rarely due to toxicity

65
Q

MAO-B inhibitors place in therapy

A

rasagiline, selegiline, safinamide

first line for mild symptoms

second line for adjunctive therapy

manage LD motor fluctuations

adjunctive for PD depression

66
Q

Side Effects: MAO-B inhibitors

A

n/v
headach
insomnia (selegiline)
hypo/pertension

67
Q

Starting Dose: rasagiline

A

0.5 mg po daily

68
Q

starting dose: selegiline

A

5 mg po bid

69
Q

starting dose: safinamide

A

50 mg po daily

70
Q

Clinical Pearls: MAO-BIs

A

risk of serotonin syndrome with drug-drug interactions

dextromethorphan
serotenergic antidepressants
serotonergic opioidsC

71
Q

COMT Inhibitors Place in Therapy

A

entacapone, opicapone, tolcapone

in combo to manage symptoms fluctuation (wearing off)

72
Q

Side Effects: COMT inhibitors

A

N/V
brown/orange urine discoloration (entacapone)

heptotoxicity (tolcapone)

73
Q

Starting Dose: entacapone

A

200 mg PO with each CD/LD dose

74
Q

Starting Dose: tolcapone

A

100 mg PO TID

75
Q

Starting Dose: opicapone

A

50 mg po QHS

76
Q

Clinical Pearl: COMT Inhibitor

A

in early PD, no benefit of COMT inhibitors with CD/LD compared to CD/LD alone

77
Q

Amantadine Place in Therapy

A

Management of LD motor fluctuations

modest effect in controlling motor symptoms, but rarely used monotherapy

78
Q

Amantadine Side Effects

A

insomnia

confusion/hallucinations

livedo reticularis

79
Q

Amantadine Clinical Pearls

A

usually reserved CD/LD peak dose dyskinesias

80
Q

Starting Dose Amantadine

A

100 mg po BID

81
Q

Anticholinergics Place in Therapy

A

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
Q

Starting Dose: benztropine

A

0.5 mg po qhs

83
Q

starting dose: trihexyphenidyl

A

1 mg po daily

84
Q

Constipation

A

increase fluid intake, physical activity if able

stool softeners/laxatives or probiotics

85
Q

Insomnia

A

avoid benzos (diazepam, lorazepam)

86
Q

Orthostatic Hypotension

A

non pharm counseling
midodrine/droxidopa

87
Q

Anxiety/Depression

A

SSRI/SNRI
Avoid: benzos
CBT

88
Q

Dementia

A

donepezil, rivastigmine
avoid: anticholinergics/benzos/antihistamines/sedatives

89
Q

psychosis/delirium

A

avoid: haloperidol, olanzapine, paliperidone, risperidone

redose PD doses
pimavanserin (antipsych for PD)
atypical antipsychs (clozapine, quetiapine)

PHRM 845 (14 decks)

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