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PR3136 > Treatment of Parkinson's Disease l > Flashcards

Treatment of Parkinson's Disease l Flashcards

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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)

Study These Flashcards
A
  1. Modify dosing interval (shorten dosing interval)

2. Use modified release > immediate release preparations

25
PD disease progression
- narrow therapeutic window - lower threshold conc for dyskinesia - higher threshold conc for symptomatic relief
26
Sustained release Levodopa purpose
- 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
Switching between immediate release agents and SR/CR Levodopa
SR/CR to IR : - decrease dose IR to SR/CR : - increase dose (25-50%)
28
Sinemet SR precaution
- do not crush
29
Madopar HBS precaution
- do not open capsule
30
Levodopa DDI (5)
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
Dopamine agonists types
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
MOA dopamine agonists (2)
- act on D2 receptors in nigral striatum | - mimics dopamine
33
Dopamine agonists PK
- 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
Dopamine agonists ADR (dopaminergic) - Peripheral - Central
Peripheral (3) - N/V - postural hypotension - leg oedema ``` Central (3) - daytime drowsiness, somnolence - hallucinations (visual > auditory) - compulsive behaviours eg gambling, shopping, eating & hypersexuality ```
35
Dopamine agonists ADR (non-dopaminergic) (2)
Higher risks for ergot derivative 1. Fibrosis - may be partially reversible upon withdrawal - pulmonary, pericardiac, retro-peritoneal 2. Valvular heart disease
36
Dopamine agonists vs Levodopa (4) - patients type - ADR
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
Why is dopamine agonists > Levodopa in younger patients? (2)
1. To maximise treatment options | 2. To delay the onset of Levodopa-induced motor complications
38
Dopamine agonists place in management of PD (3)
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
Rotigotine patch uses
- used in patients not suitable for tube-feeding, cannot swallow and transition - NIL by mouth - not registered in SG anymore
40
Rate of regeneration of MAOs
14-28 days cos irreversible inhibition
41
MAO-A metabolism
- peripheral - NA - 5-HT
42
MAO-B metabolism
- central | - dopamine
43
MAO-Bi examples (2)
1. Selegiline 2. Rasagiline - irreversible
44
MAO-B i use in PD (2)
- 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
Selegiline metabolism
- hepatically metabolised to amphetamines (stimulating but no effect on MAO-B)
46
Rasagiline metabolism
- not metabolised to amphetamines
47
DDI of MAO-B i (7)
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
FDI of MAO-B i
- food rich in tyramines | - advice patients to avoid such foods
49
MAO-B i vs Dopamine agonists & Levodopa
MAO-B i < Dopamine agonists & Levodopa
50
COMT meaning
Catechol-O-methyl Transferase
51
COMT-i examples (2)
1. Entacapone | 2. Tolcapone (not in SG)
52
COMT-i MOA
- 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
COMT-i clearance
Hepatic metabolism
54
COMTi ADR (6)
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
Entacapone DDI
- avoid with MAOi
56
Tolcapone vs Entacapone (3)
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
Early/young onset vs Late onset of PD (2)
Early/young onset - less cognitive decline - common presentation is dystonia Late onset - more cognitive decline - common presentation (2/3 of cardinal features)
58
Management of tardive dyskinesia (3)
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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