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PR3136 PT IV > Idiopathic PD > Flashcards

Idiopathic PD Flashcards

1
Q

What is Parkinson’s Disease/ paralysis agitans/ shaking palsy?

A
  • idiopathic
  • degenerative
  • CNS disorder
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2
Q

What are the 4 characteristic features of PD?

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

What are the 3 cardinal signs that are used for diagnosis of PD?

A
  • Tremor: resting tremor (disappears with movement), inc w stress
  • Rigidity: “ratchet”-like stiffness (cogwheel rigidity); also leadpipe rigidity
  • Akinesia/bradykinesia: subjective sense of weakness, loss of dexterity, difficulty using kitchen tools, loss of facial expression, reduced blinking, difficulty getting out of bed/chair, difficulty turning while walking
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4
Q

How many cardinal signs must be present to confirm diagnosis of PD?

A

2 out of 3

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5
Q

Which cardinal sign is not a diagnostic feature?

A

Postural instability

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6
Q

What are the features at initial presentation of Idiopathic PD?

A
  • Asymmetric
  • +VE response to levodopa / apomorphine
  • Postural instability (& falls) - not present
  • Less rapid progression (rapid is H&Y of 3 in 3 years)
  • Autonomic dysfn - not present
  • Impaired olfaction (?)
  • Neuroimaging ??
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7
Q

What are some morbidity factors caused by Idiopathic PD?

A
  • Unable to perform basic ADLs (or perform them safely)
    ~ mobility, feeding self, grooming, personal hygiene, toileting, showering/bathing, continence (bowel and bladder)
  • Dysphagia (leads to pneumonia)
  • Falls due to instability (not able to react fast enough)
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8
Q

What is the cause of Idiopathic PD?

A
  • Loss of dopaminergic neurons in substantia nigra: about 80% loss –> clinical smx
  • age-related loss of neurons
  • env toxin/insults?; MPTP-MPP+, Pesticides, herbicides
  • genetics: predisposition to toxins/ insults; genetic abnormalities
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9
Q

When do we use Hoehn and Yahr to measure PD?

A
  • to assess mobility (doesnt measure non-motor smx)
  • if on tx, should be assess when the person is in the “ON” and also in the “OFF” state
    (dont need to do at every clinic visit)
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10
Q

How to we interpret Hoehn and Yahr? (KIV)

A

increasing disability; decreasing independence from 1 to 5

1: smx on one side of body only

2: bilateral smx; no balance impairment
3: impaired postural reflexes; physically independent
4: Severe disability, yet still able to walk/ stand or stand unassisted

5: wheelchair bound or bedridden

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11
Q

What are some non-motor smx of PD?

A
  • dementia
  • depression
  • psychosis
  • REM sleep behaviour disorder
  • Constipation
  • GI motility
  • Orthostatic hypotension
  • Sialorrhoea (due to dysphagia)
  • Fatigue
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12
Q

What are other measurements for PD? KIV

measuring non-motor sx

A
  • UPDRS

- MDS-UPDRS (+non-motor)

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13
Q

How many years before clinical onset does smx occur?

A

20 year prodrome:

  • 20yr hyposmia (lack of smell), constipation, bladder disorder
  • 10yr sleep disorder, obesity, depression
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14
Q

What are the features of early/ young onset PD?

A
  • slower disease progression

Features:

  • less cognitive decline
  • earlier motor complications
  • dystonia common initial presentation VS falls & freezing in late-onset

dopamine agonists used in preference to levodopa

  • dystonia (muscles contract involuntarily, causing repetitive or twisting movements.)
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15
Q

What are the goals of tx?

A

Manage smx
Maintain fn and autonomy

no tx for PD has ever been shown to be “neuroprotective”

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16
Q

Which class of drugs inc central dopamine, dopaminergic transmission?

A

1) levodopa + DCI
2) Dopamine agonists
3) MAO B inhibitors
4) COMT inhibitors

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17
Q

Which class of drugs correct the imbalance in other pathways?

A

1) Anticholinergics

2) NMDA antagonists

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18
Q

What are some non-pharmacological approaches to PD?

A
  • PT: stretching, transfers, posture, walking
  • OT: mobility aids, home and workplace safety
  • speech and swallowing
  • surgery
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19
Q

When is levodopa most effective?

A
  • esp Bradykinesia and Rigidity
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20
Q

When is levodopa the least effective?

A
  • less effective for speech, postural reflex and gait disturbances
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21
Q

Why dopamine cannot be used as a treatment?

A

DA doesnt cross BBB

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22
Q

Which enzyme causes a peripheral conversion of levodopa to dopamine?

A
  • Catalysed by DOPA decarboxylase, MAO, COMT
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23
Q

What are the PK of levodopa?

A
  • abs in proximal part of SI
  • Levodopa F: ~ 33%
  • With benserazide or carbidopa: ~75%
  • by an active saturable carrier system for large neutral aa e.g. tryptophan
  • Abs dec with high fat or high protein meals (separate by 2 hours)
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24
Q

What is combined with Levodopa?

A

DOPA decarboxylase inhibitors (DCI)

  • Do not cross the BBB (only protect levodopa at peripheral)

75-100mg daily required to saturate dopa decarboxylase

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25
Q

What is the ratio of DCI: levodopa?

A

DCI: levodopa

  • 1:4 (Sinemet, Madopar)
  • 1:10 (Sinemet)
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26
Q

What are the adv effects of levodopa?

A
  • N/V
  • Orthostatic hypotension
  • Drowsiness, sudden sleep onset
  • Hallucinations, psychosis
  • Dyskinesias - Usual onset: within 3-5 yrs of initiating tx w levodopa
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27
Q

What are some motor complications of levodopa?

A
  • “on-off” phenomenon
  • “wearing off”
  • dyskinesias
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28
Q

What is the “on-off” phenomenon?

A

“on-off” phenomenon

  • ON: response to levodopa
  • OFF: no response to levodopa
  • Unpredictable, not related to dose/ dosing interval
  • “throwing a light switch”
  • Mechanism is unclear
  • Difficult to control w meds
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29
Q

What is the “wearing off” effect of levodopa and how do we manage it?

A

“wearing off”

  • Effect of levodopa wanes before the end of the dosing interval
  • shortened “ON” time
  • associated with disease progression
  • Management: Modify times of adm, and/or Replace with modified-release preparations at the appropriate time
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30
Q

What is dyskinesia and how to manage it?

A
  • involuntary, uncontrollable
  • twitching, jerking
  • peak dose dyskinesia
  • dystonia

Management: add amantadine; or replace specific doses with modified-release levodopa

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31
Q

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

A
  1. Early PD
    Long duration motor response –> Low incidence of dyskinesia
  2. Moderate PD
    Shorter duration motor response –> Increased incidence of dyskinesia
  3. Advanced PD
    Short duration motor response –> ‘On’-time consistently associated with dyskinesia
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32
Q

Why are sustained-release forms of levodopa designed?

A

release levodopa/DCI over a longer period (about 4-6 hours)

SR have Lower F

  • dose adjustments may be needed when switching between IR (immediate-release) and CR (controlled-release) forms
  • IR to CR: generally inc dose needed (~25-50%)
  • CR to IR: generally dec dose needed
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33
Q

What are some precautions/ instructions for sustained-release levodopa?

A

useful for dec stiffness on waking (to be taken before bedtime)

Sinemet SR/CR - do not crush
Madopar HBS -do not open capsule

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34
Q

What are some DDI/ food-drug interactions that we should monitor/consider for levodopa?

A
  • pyridoxine
  • iron
  • protein
  • antidopaminergic drugs
  • nonselective MAOis
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35
Q

What is the concern between Pyridoxine and Levodopa?

A

Pyridoxine (B6) is a cofactor for dopa decarboxylase

  • generally not a problem if levodopa is adm w DCI BUT to be aware of possibility of interactions with:
  • high dose of B6 for haematological problems or in high potency Vit B complex tabs
    (e. g. Neurobion, vit b4, daneuron)
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36
Q

What is the concern between Iron and Levodopa?

A

Iron affects abs of levodopa –> space out adm

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37
Q

What is the concern between Protein (food, protein powder) and Levodopa?

A

Affects abs of levodopa –> space out adm (2 hours apart)

38
Q

What is the concern between Antidopaminergic drugs and Levodopa?

A

NO: Metoclopramide, prochlorperazine, 1st gen antipsychotics, risperidone

Antiemetic of choice in PD (for N/V) = DOMPERIDONE

39
Q

What are the ergot and non-ergot derivatives of dopamine agonists?

A

Ergot derivatives:

  • Bromocriptine
  • Cabergoline
  • Pergolide (not in SG)

Non-ergot derivatives:

  • Ropinirole
  • Pramipexole
  • Rotigotine (transdermal patch)
  • Apomorphine (subcut, injection, not in SG)
40
Q

What is the MOA of dopamine agonists?

A

Act on D2 receptors in the basal ganglia

Mimic action of dopamine

41
Q

What are the PK of dopamine agonists?

A

Ergot derived: lower F than non-ergot derived, due to extensive first-pass metabolism

Longer t1/2 and DOA than levodopa
(Longer DOA ; prevent delay of dyskinesia, purposeless, not reversible
Dopamine agonists less likely to cause dyskinesia vs levodopa)

42
Q

Which dopamine agonist needs to be considered for dose adjustment in hepatic impairment?

A

Ropinirole: mainly metabolised by liver, to inactive metabolites

43
Q

Which dopamine agonist needs to be considered for dose adjustment in renal impairment?

A

Pramipexole: excreted largely unchanged in the urine

44
Q

What are the peripheral adv effects of dopamine agonists?

A
  • N/V
  • Orthostatic hypotension
  • Leg oedema
45
Q

What are the central adv effects of dopamine agonists?

A
  • Hallucinations (usually visual > auditory)
  • Somnolence, day-time sleepiness
  • Compulsive behaviours (gambling, shopping, eating, hypersexuality)
46
Q

What are some non-dopaminergic adv effects of dopamine agonists?

A
  • Fibrosis
    : pulmonary, pericardiac, retro-peritoneal
    : may be partially reversible upon withdrawal
    : lower risk with non-ergot agents
  • Valvular heart disease: incidence appears to be greater with ergot-derived agents

fibrosis and valvular heart disease greater w ergot-derived agents

47
Q

What are the pros and cons of levodopa and dopamine agonists?

A

dopamine agonists have less motor complications than levodopa BUT

dopamine agonists have more hallucinations, sleep disturbances, leg oedema, and orthostatic hypotension

48
Q

Is dopamine agonist preferred over levodopa?

A
  • no clinically significant differences in efficacy btw agents
  • however, dopamine agonists are freq preferred over levodopa in younger pts: to maximise tx options and delay the onset of levodopa-induced motor complications
49
Q

Is dopamine agonists used mono or combined?

A
  • monotherapy in young-onset PD

- Adjunct to levodopa in moderate/severe PD

50
Q

How does dopamine agonist help with the complications of levodopa?

A

Management of motor complications caused by levodopa

51
Q

When is the Rotigotine patch used for?

A

Useful when transferring

Handy for pts not suitable for those cant take things orally,
Nil by mouth, cannot be tube fed

52
Q

Is it proven that dopamine agonists have neuroprotective effects and have disease modifications?

A

no

53
Q

What are some additional points to note for dopamine agonists (KIV?)

A
  • pergolide not registered in SG
  • Rotigotine patches: in some countries, the patch required refrigeration. The manufacturer has de-registered Neupro patches in SG –> exemption item

Cabergoline marketed under 2 diff brand names: Dostinex (0.5mg); Cabaser (1mg, 2mg) ; Cabaser not registered in SG

Pramipexole and Ropinirole are available in both IR and SR forms

54
Q

What are the MAO-B inhibitors?

A

central, dopamine (HOWEVER, not totally selective for MAO-B)

NOT peripheral, NE and 5HT (MOA-A)

Rate of MAO regeneration: 14-28 days

55
Q

Which MAO-B inhibitors are irreversible enzyme inhibitors?

A

Selegiline and Rasagiline

56
Q

What is unique about the t/2 and DOA of Selegiline and Rasagiline?

A

Short half life (~1.5-4hrs)

BUT long DOA

57
Q

Are Selegiline and Rasagiline used mono or combi with levodopa?

A
  • MONOtherapy used for early stages
58
Q

Is it proven that MAO-B inhibitors have neuroprotective effects?

A

no

59
Q

What are the doses of Selegiline and Rasagiline?

A

Selegiline: 5mg OM to BD (2nd dose in the afternoon)

Rasagiline: 0.5mg to 2mg OD (any time of the day)

60
Q

Which MAO-B inhibitor is hepatically metabolised to amphetamines which are stimulating and thus have no effect on MAO-B?

A

Selegiline

61
Q

Which MAO-B inhibitor is not metabolised to amphetamines?

A

Rasagiline

62
Q

What is the problem with the formation of amphetamines?

A

stimulating and have no effect on MAO-B

63
Q

What are some DDI interactions with MAO-B inhibitors?

A

Drug interactions:
- SSRIs, SNRIs, TCAs: washout periods recommended

  • Pethidine, tramadol
  • Linezolid
  • Dextromethorphan
  • Dopamine
  • Sympathomimetics: nasal decongestants e.g. pseudoephedrine, phenylephrine
  • another MAOI
64
Q

What are some drug-food interactions with MAO-B inhibitors?

A

Tyramine: metabolised by both MAO-A and MAO-B

No firm guidelines regarding the necessity for dietary restriction

In practice, pts should be advised to avoid such foods

65
Q

How to use MAO-B inhibitors to manage PD? mono or combi and at which stage of PD is it usually used?

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
66
Q

Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more improvement in motor smx

A

levodopa

67
Q

Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more improvement in ADLs?

A

levodopa

68
Q

Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more motor complications?

A

levodopa

69
Q

Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more specific adv effects?

A

dopamine agonists

70
Q

In the presence of DCI (Decarboxylase inhibitor), which enzyme is a major metaboliser of levodopa?

A

COMT

71
Q

What COMT inhibitors do? MOA?

A
  • decreases “off” time; Useful in wearing off, prolonged effect of levodopa
72
Q

Is COMT inhibitor used as mono or combi?

A

Not effective without concurrent levodopa
“protects levodopa”

In animals, shown to inhibit central COMT activity

COMT activity; enters CNS minimally; protects levodopa in the peripheral

73
Q

What is entacapone?

A

Selective, reversible COMT inhibitor

TO BE TAKEN AT SAME TIME AS LEVODOPA

74
Q

What are some DDI to take note of for entacapone?

A
  • iron, calcium chelation
  • any catecholamine drug
  • enhance anticoagulant effect of warfarin

Not applicable in SG: Avoid concurrent nonselective MAOi (but safe with MAO-B inhibitors, caution with selectiv e MAO-Ai)

75
Q

What are some side effects of entacapone?

A 
diarrhoea
urine discolouration (orange)
76
Q

Is entacapone “with caution” in hepatic or renal impairment?

A

hepatic impairment

77
Q

Do we need to monitor LFTs for Entacapone?

A

No

78
Q

What are the 2 forms of Entacapone?

A
  • Comtan: entacapone ONLY
    Entacapone only given when you want to longer duration by reducing the conversion of levodopa to dopamine
  • Stalevo: levodopa, carbidopa, and entacapone (to lengthen DOA)
79
Q

What are some adv effects of entacapone?

A
  • may cause dyskinesia upon initiation –> may require a dec in levodopa dose (Usually reversible, for a short period of time)
  • May also potentiate other dopaminergic effects: orthostatic hypotension, N/V (more sig SE)
80
Q

What are some common side effects of Anticholinergic drugs?

A

Dry mouth

constipation

Urinary retention

Blurred vision, confusion

81
Q

Is the site of action of anticholinergics at CNS or periphery?

A

CNS

PD is a CNS disorder

82
Q

Which drugs cannot be used to manage smx of PD?

A

Peripherally acting agents such as

Ipratropium and Hyoscine N-butylbromide (polar, hydrophilic, doesnt cross BBB)

Tolterodine: bladder issues

83
Q

What are the 2 anticholinergic drugs used for PD?

A
  • Benztropine (tmax 7h)

- Trihexyphenidyl (tmax 1.3h)

84
Q

What are NMDA?

A

NMDA N-methyl-D-asparate

  • One of the chemicals associated with neurotoxicity is glutamate
  • Glutamate activates NMDA receptor activity which activates processes that encourage cell death
  • Inc glutamatergic activity linked to the : development of, and Maintenance of levodopa-induced dyskinesia
85
Q

What is amantadine?

A
  • NMDA antagonist
  • anticholinergic
  • upregulates D2 receptors, inc sensitivity of D2 receptors

several proposed MOA
good evidence for an effect on levodopa-induced dyskinesia

86
Q

Does memantine have a good evidence for an effect on levodopa-induced dyskinesia?

A

no

87
Q

How are NMDA antagonists excreted?

A

Renally excreted - reduce dose in renal impairment

88
Q

How are the doses like for NMDA antagonists?

A

Can be stimulating (similar to the formation of amphetamines in MAOB)

  • 2nd dose in the afternoon, NOT AT NIGHT
89
Q

Can amantadine given with memantine?

A

no, avoid concurrent use with memantine

90
Q

What are the adv effects of NMDA antagonists?

A

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

91
Q

Is NMDA antagonist mono or combi or adjunctive?

A
  • adjunctive

- managing levodopa-induced dyskinesias

92
Q

What are some alternative / complementary med we should look out for?

A
  1. Co-enzyme Q10 + 200iU vit E in early PD –> safe but not effective
  2. Creatine for tx of early stage PD –> safe but not effective
  3. Vit E
  4. Glutathione
  5. Ribofalvin
  6. Lipoic acid
  7. Acetyl carnitine
  8. Curcumin

PR3136 PT IV (17 decks)

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