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PR3136 > Treatment of Parkinson's Disease l > Flashcards

Treatment of Parkinson's Disease l Flashcards

1
Q

Potential diagnosis of patients with parkinsonian symptoms

A
  1. Idiopathic PD
  2. Parkinson’s Plus
    - have specific symptoms
  3. Parkinsonism
    - drug-induced
    - toxin-induced
    - vascular
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2
Q

Parkinson’s Disease features

A
  • idiopathic
  • neurodegenerative
  • CNS disorder
  • 4 characteristic features :
    1. Muscular rigidity
    2. Rest tremors
  • disappears with movement
    3. Slow movements & poverty of movement (bradykinesia)
    4. Postural instability
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3
Q

Diagnosis of PD

A
  1. Clinical signs, physical examinations & history

- must have at least 2 of the 3 cardinal signs (tremors, rigidity & bradykinesia/akinesia)

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4
Q

Akathesia = Akinesia?

A

No.
Akinesia is no movement
Akathisia is movement disorder that makes it hard to stay still

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5
Q

Dyskinesia = Bradykinesia?

A

No.
Dyskinesia is involuntary movements
Bradykinesia is slow movement

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6
Q

IDP INITIAL clinical presentations (3)

A
  1. Asymmetric
  2. Positive response to Levodopa / Apomorphine (dopamine agonist)
  3. Less rapid progression (rapid = H&Y 3 in 3 years)
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7
Q

Morbidities of IDP (3)

A
  1. Unable to perform ADL or unable to perform ADL safely
  2. Dysphagia
    - increase risk of pneumonia
  3. Falls
    - due to gait instability
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8
Q

Pathological cause of IDP (3)

A

At least 50-80% loss of dopaminergic neurones in substantia nigra

  • leads to clinical symptoms
    1. Age-related loss of neurons
    2. Environmental toxin/insult
  • pesticides/herbicides
    3. Genetics
  • genetics abnormalities
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9
Q

H&Y staging (5)

A

H&Y 1
- symptoms on one side of body

H&Y 2

  • symptoms on both sides of body
  • no balance impairment

H&Y 3

  • balance impairment
  • physically independent

H&Y 4
- severe disability but still can walk/stand unassisted

H&Y 5

  • wheelchair bound
  • bedbound
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10
Q

Measuring PD using H&Y staging (3)

A
  • assess mobility
  • if not on treatment, assess when the person is in “on” and “off” state
  • no need to reassess on every visit
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11
Q

Non-motor symptoms of PD (4)

A
  1. Psychiatric impairment
    - depression
  2. Cognitive impairment
    - dementia
  3. Sleep disorders
  4. Autonomic dysfunction
    - constipation
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12
Q

PD rating scales (3)

A
  1. H&Y
  2. Unified Parkinson’s Disease Rating Scale (UPDRS)
  3. MDS-UPDRS
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13
Q

Is there predromal symptoms of PD?

Examples of predromal symptoms (3)

A

Possible.
Can be unmasked by drug-induced parkinsonism
eg hyposmia, constipation, bladder disorder

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14
Q

Early/Young onset of PD

A
  • slower disease progression
  • common initial presentation is dystonia (compared to falls & freezing in late-onset)
  • less cognitive decline but earlier motor complications
  • treatment : dopamine agonist > levodopa
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15
Q

Goal of PD treatment (2)

A
  1. Manage symptoms

2. Maintain function & autonomy (increase independence)

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16
Q

Can PD treatment cure PD?

A 
No.
There is no treatment for PD that has clear evidence to be neuroprotective.
PD treatment cannot :
- replace dopamine
- cure PD
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17
Q

Pharmacological treatments for PD (6)

A

Increase central dopamine, dopaminergic transmission

  1. Levodopa + peripheral decarboxylase inhibitor (DCI)
  2. Dopamine agonist
    - ergot-derivative (bromocriptine, cabergoline, pergolide)
    - non-ergot derivative (ropinirole, pramipexole, apomorphine, rotigotine)
  3. COMT-i
    - Entacapone
    - Tolcapone (not in SG)
  4. MAO-i
    - Selegiline (stimulating)
    - Rasagiline
    Correct imbalance in other pathways
  5. Acetylcholinergics
    - Benztropine
    - Trihexyphenidyl
  6. NMDA antagonists
    - Amantadine
    - Memantine
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18
Q

Non-pharmacological treatment for PD

A

Involve several professionals as the impact of PD is wide

eg physiotherapy, speech therapy, nutrition therapy, occupational therapy

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19
Q

Why dopamine cannot be used a direct treatment?

A

Dopamine cannot cross BBB.

Hence DCI added tgt with Levodopa to prevent peripheral metabolism of Levodopa to dopamine

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20
Q

Peripheral conversion of Levodopa to dopamine & potential ADR

A

Catalysed by :

  • MAO
  • COMT
  • dopamine decarboxylase

SE :
N/V & postural hypotension due to dopamine production

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21
Q

Levopdopa PK (2)

A
  • F (levodopa) = 33%
  • F (levodopa + DCI) = 75%
  • absorption by active saturable carrier system for large neutral amino acids (eg tryptophan)
    Hence, FDI w high protein food (reduce F)
    Space apart 2h
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22
Q

Preparations of available DCI : Levodopa (3)

A

Sinemet 1:4
Sinemet 1:10
Madopar 1:4

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23
Q

Levodopa ADR (7)

A
  1. N/V
  2. Orthostatic hypotension
  3. Drowsiness, sudden sleep onset
  4. Hallucinations, psychosis
  5. Dyskinesia (3-5years onset after taking drug)
  6. “on-off” phenomenon
    - unpredictable
  7. “wearing off” phenomenon
    - disease progression
    - decreased plasma conc at end of dose
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24
Q

Management of “wearing off” phenomenon (2)

A
  1. Modify dosing interval (shorten dosing interval)

2. Use modified release > immediate release preparations

25
Q

PD disease progression

A
  • narrow therapeutic window
  • lower threshold conc for dyskinesia
  • higher threshold conc for symptomatic relief
26
Q

Sustained release Levodopa purpose

A
  • designed to release Levodopa/DCI over a longer period of time (4-6h)
  • reduce risk of “wearing off” effects
  • useful to reduce stiffness on walking
  • lower bioavailability
27
Q

Switching between immediate release agents and SR/CR Levodopa

A

SR/CR to IR :
- decrease dose

IR to SR/CR :
- increase dose (25-50%)

28
Q

Sinemet SR precaution

A
  • do not crush
29
Q

Madopar HBS precaution

A
  • do not open capsule
30
Q

Levodopa DDI (5)

A
  1. Vit B6 (pyridoxine)
    - cofactor for doapamine decarboxylase
    - generally not an issue if using DCI but do be aware of possibility of interactions with high dose vitB6 & high potency vitB complex tablets
  2. Iron
    - chelates with iron to decrease F
    - space out administration
  3. Protein
    - absorption of Levodopa is by saturable carrier systems for large neutral AA
    - space out administration 2h
  4. Antidopaminergic drugs
    eg metoclopramide, prochlorperazine, 1st gen antipsychotics (FGA) & risperidone
    - antiemetic use domperidone
  5. Non-selective MAOi (not registered in SG)
31
Q

Dopamine agonists types

A
  1. Ergot derivatives
    - bromocriptine
    - cabergoline (Dostinex)
    - pergolide (not in SG)
  2. Non-ergot derivative
    - ropinirole (SR & IR available)
    - pramipexole (SR & IR available)
    - apomorphine (SC)
    - rotigotine (transdermal) (not in SG)
32
Q

MOA dopamine agonists (2)

A
  • act on D2 receptors in nigral striatum

- mimics dopamine

33
Q

Dopamine agonists PK

A
  • ergot derivative F < non-erogt derivative F due to extensive 1st pass metabolism
  • longer half life & duration of action that Levodopa
  • hepatic metabolism (ropinirole)
  • renal excretion (pramipexole)
34
Q

Dopamine agonists ADR (dopaminergic)

  • Peripheral
  • Central
A

Peripheral (3)

  • N/V
  • postural hypotension
  • leg oedema
Central (3)
- daytime drowsiness, somnolence
- hallucinations (visual > auditory)
- compulsive behaviours
eg gambling, shopping, eating & hypersexuality
35
Q

Dopamine agonists ADR (non-dopaminergic) (2)

A

Higher risks for ergot derivative

  1. Fibrosis
    - may be partially reversible upon withdrawal
    - pulmonary, pericardiac, retro-peritoneal
  2. Valvular heart disease
36
Q

Dopamine agonists vs Levodopa (4)

  • patients type
  • ADR
A
  1. Dopamine agonists less motor complications than Levodopa
  2. Dopamine agonists more hallucinations, sleep disturbances & leg oedema than Levodopa
  3. Dopamine agonists preferred in younger patients than Levodopa
  4. No clinical significant difference in efficacy between both agents
37
Q

Why is dopamine agonists > Levodopa in younger patients? (2)

A
  1. To maximise treatment options

2. To delay the onset of Levodopa-induced motor complications

38
Q

Dopamine agonists place in management of PD (3)

A
  1. Monotherapy in younger patients
  2. Adjunct to Levodopa in moderate/severe PD
  3. Can be used to manage the motor complications caused by Levodopa
39
Q

Rotigotine patch uses

A
  • used in patients not suitable for tube-feeding, cannot swallow and transition
  • NIL by mouth
  • not registered in SG anymore
40
Q

Rate of regeneration of MAOs

A

14-28 days cos irreversible inhibition

41
Q

MAO-A metabolism

A
  • peripheral
  • NA
  • 5-HT
42
Q

MAO-B metabolism

A
  • central

- dopamine

43
Q

MAO-Bi examples (2)

A
  1. Selegiline
  2. Rasagiline
  • irreversible
44
Q

MAO-B i use in PD (2)

A
  • effective as monotherapy in early stages
  • adjunct in later stages
  • not totally selective for MAO-B (can cross over to MAO-A)
  • no evidence of neuroprotection
45
Q

Selegiline metabolism

A
  • hepatically metabolised to amphetamines (stimulating but no effect on MAO-B)
46
Q

Rasagiline metabolism

A
  • not metabolised to amphetamines
47
Q

DDI of MAO-B i (7)

A
  1. SSRI, SNRI, TCAs (washout period req)
  2. Tramadol, pethidine (opioids)
  3. Dextromethorphan
  4. Dopamine
  5. Sympathomimetics (eg pseudoephedrine, phenylephrine)
  6. Another MAO-i
  7. Linezolid
48
Q

FDI of MAO-B i

A
  • food rich in tyramines

- advice patients to avoid such foods

49
Q

MAO-B i vs Dopamine agonists & Levodopa

A

MAO-B i < Dopamine agonists & Levodopa

50
Q

COMT meaning

A

Catechol-O-methyl Transferase

51
Q

COMT-i examples (2)

A
  1. Entacapone

2. Tolcapone (not in SG)

52
Q

COMT-i MOA

A
  • decrease “off” times & “wearing off” effect by inhibiting COMT metabolism of levodopa
  • major metaboliser of Levodopa in the presence of DCI
  • not effective without concurrent Levodopa
  • selective, reversible COMTi
  • must be taken at the same time as Levodopa
53
Q

COMT-i clearance

A

Hepatic metabolism

54
Q

COMTi ADR (6)

A
  1. Diarrhoea (entacapone)
  2. Urine discoloration (orange) (entacapone)
    - Levodopa also cause urine discoloration
  3. Dyskinesia upon initiation (reversible)
    - may need to decrease Levodopa dose
  4. N/V
  5. Orthostatic hypotension
  6. Hepatic impairment
    - LFT monitoring for Tolcapone
    - every 2-4 weeks for 6 months
55
Q

Entacapone DDI

A
  • avoid with MAOi
56
Q

Tolcapone vs Entacapone (3)

A

Tolcapone

  • more potent and longer duration of action (2-3h)
  • Tolcapone require greater reduction in Levodopa dose
  • Tolcapone require LFT every 2-4 weeks for 6 months

Entacapone

  • less potent and shorter duration of action (1-2h)
  • Entacapone require smaller reduction in Levodopa dose
  • Entacapone does not require regular LFT monitoring
57
Q

Early/young onset vs Late onset of PD (2)

A

Early/young onset

  • less cognitive decline
  • common presentation is dystonia

Late onset

  • more cognitive decline
  • common presentation (2/3 of cardinal features)
58
Q

Management of tardive dyskinesia (3)

A
  1. Modified release > immediate preparations (prevention)
  2. Immediate release (acute symptomatic treatment)
  3. Amantadine (maintenance of progression of levodopa-induced dyskinesia)

PR3136 (19 decks)

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