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PR3136 therapeutics > PD > Flashcards

PD Flashcards

1
Q

Describe how PD affects basic ADLs

A

Unable to perform basic ADLs (or to perform them safetly)

  • Mobility (walking, using stairs)
  • Feeding self
  • Grooming, personal hygiene
  • Toileting
  • Showering/bathing
  • Continence (bowel and bladder)

Dysphagia (→ pneumonia)

Falls (due to gait instability)

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2
Q

Explain the goal of managing PD

A

Not replace dopamine or cure

But to manage symptoms and maintain function & autonomy

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3
Q

What is Parkinson’s disease?

A

Idiopathic, degenerative, CNS disorder with 4 characteristic features

  1. Slowness and poverty of movement
  2. Muscular rigidity
  3. Resting tremor
  4. Postural instability
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4
Q

How is a diagnosis for PD made?

A

Based on clinical signs, physical examination, history.
2 of the 3 cardinal signs must be present:
- Tremor (resting tremor)
- Rigidity (“ratchet” like stiffness)
- Akinesia/bradykinesia

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5
Q

Features of idiopathic PD at initial presentation

A
  • Asymmetric
  • Positive response to levodopa or apomorphine
  • Postural instability (&falls) - not present
  • Less rapid progression (rapid = H&Y 3 in 3 years)
  • Autonomic dysfunction - not present
  • Neuroimaging - may not be able to see anything on neuroimaging
  • Impaired olfaction?
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6
Q

Pathology of PD

A

Loss of dopaminergic neurons in the substantia nigra
about 80% loss → clinical symptoms

  • Age-related
  • Environmental toxin/insults
  • Genetics
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7
Q

What is used to measure PD? What does it measure?

A

Hoen and Yahr staging of PD
1-5
(1 is mildest symptoms, 5 is most severe symptoms)
Assesses mobility (not nonmotor symptoms)

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8
Q

How many % of neurons need to be lost before seeing symptoms?

A

80%

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9
Q

Which agents are used in early/young onset PD?

A

Dopamine agonists used in preference to levodopa due to longer elimination half life or duration of action, and prevent the development of dyskinesia

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10
Q

Features of early/young onset PD

A 
Slower disease progression 
Features 
- Less cognitive decline
- Earlier motor complications
- Dystonia is common initial presentation vs falls and freezing in late onset
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11
Q

Which agent can be used to prevent nerves from degenerating, i.e. neuroprotective agent?

A

No treatment for PD has ever been shown to be “neuroprotective”

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12
Q

Are non-pharmacologic treatments important in the management of PD? What are some examples?

A

Yes. helps patients cope with symptoms.

  • PT - stretching, transfers, posture walking
  • OT - mobility aids, home and workplace safety
  • Speech and swallowing
  • Surgery
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13
Q

Pharmacological management of PD

A

Increase central dopamine, dopaminergic transmission

  • Levodopa + DCI
  • Dopamine agonists
  • MAO B inhibitors
  • COMT inhibitors

Correct imbalance in other pathways

  • Anticholinergics
  • NMDA antagonists
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14
Q

MOA of PD pharmacologicals

A

Increase central dopamine
Increase dopaminergic transmission
Correct imbalance in other pathways

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15
Q

What symptoms are levodopa most effective and less effective in treating?

A

More effective in bradykinesia and rigidity

Less effective for speech, postural reflex and gait disturbancs

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16
Q

Why do we need to administer levodopa with DCI?

A

Dopamine cannot cross the BBB

Peripheral conversion of levodopa to dopamine is catalysed by DOPA decarboxylase, MAO, COMT

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17
Q

How to increase bioavailability of levodopa?

A

Add benserazide or carbidopa

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18
Q

How is absorption of levodopa affected by high fat or high protein meals? Implication?

A

Levodopa is absorbed by an active saturable carrier system for large neutral amino acids

If patients are required to be on high protein meals, need to seperate the administration of both by at least 2 hours.

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19
Q

What are the targets in reducing peripheral conversion of levodopa and dopamine? Examples of each?

A

Decarboxylase (carbidopa, benserazide)
COMT (entacapone)
MAO-B (selegiline)

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20
Q

Do DCIs cross the BBB?

A

No, they do not

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21
Q

Adverse effects of levodopa

A
  • Nausea and Vomiting
  • Orthostatic hypotension
  • Drowsiness, sudden sleep onset
  • Hallucinations, psychosis
  • Dyskinesias (usual onset: 3-5 years of initiating treatment with levodopa)
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22
Q

Motor complications with levodopa

A

“on-off phenomenon”
“wearing off”
Dyskinesias

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23
Q

What is the “on off phenomenon”?

A

ON = response to levodopa
OFF = no response to levodopa
Mechanism unclear

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24
Q

What is the “wearing off” phenomenon?

A

Effect of levodopa wanes before the end of the dosing interval
Shortened “ON” time
Associated with disease progression

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25
Q

How to manage “wearing off”

A

Modify times of administration

Replace with modified-release preparations at the appropriate time

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26
Q

What is dyskinesia? When does it occur and how to manage?

A

Involuntary, uncontrollable twitching and jerking
Peak dose
Management: add amantadine, replace specific doses with modified release levodopa

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27
Q

What are the changes in levodopa response associated with progression of PD?

A

In early PD: long duration of motor response, low incidence of dyskinesia
Moderate PD: shorter duration of motor response, increased incidence of dyskinesia
Advanced PD: short duration motor response, “ON”-time consistently associated with dyskinesia

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28
Q

What is the advantage of sustained release Levodopa?

A

Releases levodopa/DCI over a longer period which mitigates the wearing off effect

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29
Q

Why do dose adjustments have to be made with SR levodopa and how are they made?

A

Lower bioavailability with SR.
IR to SR: generally increase dose needed
SR to IR: generally decrease dose needed

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30
Q

Does dosing frequency change when SR formulations of levodopa are used?

A

No, frequency remains the same even in sustained release formulations

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31
Q

What is levodopa SR forms useful for?

A

Useful for reducing stiffness on waking

32
Q

What should be avoided when taking sinemet SR and madopar HBS?

A

Sinemet SR → do not crush

Madopar HBS → do not open capsule

33
Q

Drug interactions with levodopa

A
  • Pyridoxine (B6)
  • Iron (space out administration)
  • Protein (space out administration)
  • Antidopaminergic drugs - antiemetics (metoclopramide, prochlorperazine), 1st generation antipsychotics, risperidone
  • Nonselective MAOis
34
Q

What is the antiemetic of choice in PD?

A

Domperidone

35
Q

What are ergot derivative dopamine agonists?

A

Bromocriptine
Cabergoline
Pergolide (not reg in singapore)

36
Q

Non-ergot derivative dopamine agonists

A

Ropinirole
Pramipexole
Rotigotine (transdermal)
Apomorphine (subcut)

37
Q

Transdermal dopamine agonist

A

Rotigotine

38
Q

MOA of dopamine agonists

A

Act on dopamine d2 receptors in the basal ganglia and mimic action of dopamine

39
Q

Does ergot derived have higher or low F than non-ergot derived?

A

Lower, due to extensive first-pass metabolism

40
Q

How does half life and duration of action of dopamine agonists compare with levodopa?

A

Longer half life and duration of action than levodopa

41
Q

Which dopamine agonists require dose adjustments in hepatic or renal impairment?

A

Ropinirole: mainly metabolised by the liver, to inactive metabolites → dose adjust for hepatic impairment

Pramipexole: excreted largely unchanged in the urine → dose adjust for renal impairment

42
Q

Adverse effects of dopamine agonists

A

Dopaminergic - peripheral

  • Nausea, vomiting
  • Orthostatic hypotension
  • Leg edema

Dopaminergic - central

  • Hallucinations
  • Somnolence, day-time sleepiness
  • Compulsive behaviors (gambling, shopping, eating, hypersexuality)

Non-dopaminergic adverse effects

  • Fibrosis (higher with ergot)
  • Valvular heart disease (higher with ergot)
43
Q

How does dopamine agonist compare with levodopa in terms of adverse effects?

A

Less motor complications than levodopa but

More hallucinations, sleep disturbances, leg edema, orthostatic hypotension

44
Q

Dopamine agonists: place in the management of PD

A
  • Monotherapy in young-onset PD
  • Adjunct to levodopa in moderate/severe PD
  • Management of motor complications caused by levodopa
  • Rotigotine patch - if patients not suitable for tube feeding and taking things orally
  • Neuroprotection, disease modification NOT proven
45
Q

Which MAO is specific to PD

A

MAO-B (central, dopamine)

46
Q

Rate of MAO regeneration

A

14-28 days

47
Q

MAO-B inhibitors?

What kind of enzyme inhibitors are they?

A

Irreversible enzyme inhibitors

  • Selegiline
  • Rasagiline

Short half life but long duration of action (takes 2-4 weeks to regenerate)

48
Q

Are MAO-B inhibitors effective as monotherapy

A

Yes during early stages

49
Q

Why might selegiline cause insomnia?

A

It is hepatically metabolised to amphetamines which are stimulating

50
Q

Drug interactions of MAO-B inhibitors

- Not totally specific for MAO-B hence at higher doses may affect MAO-A which catalyses noradrenaline and 5HT.

A

SSRIs, SNRIs, TCAs - washout periods are recommended
Pethidine, tramadol
Linezolid
Dextromethorphan
Dopamine
Sympathomimetics: nasal congestants eg pseudoephedrine, phenylephrine
Another MAOi

51
Q

Place of MAO-B inhibitors in the management of PD

A
  • Improvement in UPDRS scores not as great as with dopamine agonists or levodopa
  • Monotherapy in early stages, or adjunct in later stages
  • More commonly used in early stages of young onset PD
52
Q

How does levodopa compare with dopamine agonists and MAO-B inhibitors?

A

More improvements in motor symptoms
More improvement in activities of daily living
More motor complications
Fewer specified adverse events

53
Q

What are COM-T inhibitors? Examples?

A

COMT is major metaboliser of levodopa in the presence of a DCI

  • Entacapone
  • Tolcapone

Decreases “off” time of levodopa
Not effective without concurrent levodopa

54
Q

What is entacapone? What are the dosing considerations?

A

Selective, reversible COMT inhibitor

must be taken at the same time as levodopa

55
Q

Drug interactions and adverse effects of entacapone

A

Drug interactions:

  • Iron, calcium
  • avoid concurrent nonselective MAOi
  • any cathecholamine drug
  • enhance anticoagulant effect of warfarin

AEs: diarrhea, urine discolouration

56
Q

Which drugs may cause dyskinesia upon initiation?

A

Entacapone

57
Q

How does tolcapone compare with entacapone?

A

More potent and longer duration of effect than entacapone

  • Less “off time:
  • May also need a greater reduction in levodopa dose
  • Need to monitor LFTs
58
Q

What is the use of anticholinergics in PD?

A

Limited use, in practice, primarily used to control tremor

59
Q

Side effects of anticholinergics

A

Constipation
Blurred vision
Urinary retention
Confusion

60
Q

Can ipratropium, hyoscine N-butylbromide, tolterodine be used to manage symptoms in PD?

A

No because it is a peripherally acting anticholinergic

61
Q

What does glutamate do?

A

Glutamate activates NMDA receptor activity which activates processes that encourage cell death.
Increased glutamatergic activity is linked to the development of, and maintenance of levodopa-induced dyskinesias

62
Q

What is amantadine’s MOA?

A

NMDA antagonist
Anticholinergic
Upregulates D2 receptors, increase sensitivity of D2 receptors

Helps to manage dyskinesia

63
Q

Amantadine dosing considerations?

A
  • Renally excreted - reduce dose in renal impairment
  • Can be stimulating, 2nd dose should be in the afternoon not night
  • Avoid concurrent use with memantine
64
Q

Adverse effects of NMDA antagonists?

A

Nausea, light-headedness, insomnia, confusion, hallucinations, livedo reticularis

65
Q

Place in therapy of amantadine in the management of PD

A

Adjunctive

Managing levodopa-induced dyskinesias

66
Q

how to distinguish Drug-induced parkinsonism from PD

A

Symptoms tend to occur bilaterally
Withdrawal of the drug usually leads to improvement in symptoms in 80% of patients in 8 weeks
Treatment should be withdrawal of offending drug

67
Q

Age correlation with parkinson disease and parkinsonism

A

Incidence of disease increases with age

68
Q

Which drugs have high risk of DIP?

A

Dopamine D2 receptor blockers

  • Typical antipsychotics (haloperidol)
  • Atypical antipsychotics (at higher doses) - risperidone, olanzapine, aripiprazole

Antiemetics such as prochlorperazine, metoclopramide

69
Q

Onset of drug-induced parkinsonism

A

~3 months within exposure to the offending agent

70
Q

Is drug-induced parkinsonism reversible?

A

Not always.

Best “treatment” = prevention

71
Q

What agents may be used for drug-induced parkinsonism?

A

Amantadine and anticholinergics

72
Q

What is parkinson hyperpyrexia syndrome caused by?

A

Changes in dopaminergic treatment
provoked by trauma, surgery and pulmonary, gastrointestinal and urinary tract infections
May have no apparent trigger

73
Q

What happens during severe cases of PHS?

A

No response to dopaminergic rescue medications, symptoms deteriorate rapidly, patient becomes progressively more immobile and rigid

74
Q

Systemic complications of PHS

A

Reduced consciousness → aspiration pneumonia
Rhabdomyolysis → ARF
Immobility → DVT, PE
DIVC

75
Q

Management of PHS

A

If cause is reduction in dopaminergic meds, reinstate previous treatment and increase dose of levodopa gradually
If PO route cannot be used, options are rotigotine patch, amantadine injection
Dantrolene, bromocriptine

76
Q

What drugs should be avoided when reviewing meds for PD patients?

A

Antidopaminergics and anticholinergics

77
Q

Complications of PD

A

Aspiration pneumonia
Dopamine agonist withdrawal
Psychosis
Dyskinesia

PR3136 therapeutics (6 decks)

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