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ESA 5 - Pharmacology > Treatment of Parkinsons Disease > Flashcards

Treatment of Parkinsons Disease Flashcards

1
Q

What kind of disorder is idiopathic Parkinsons diesae (IPD)?

A

Neurodegenerative disorder

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2
Q

What kind of clinical course does IPD take?

A

Progressive clinical course, with no cure but very slow progession, can take 20-30+ years

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3
Q

What are the motor clinical features of Parkinsonism?

A
  • Tremor
  • Rigidity
  • Bradykinesia
  • Postural instability
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4
Q

Describe the Parkinsonism tremor

A
  • Very characteristic
  • Low frequency, 3-5Hz
  • ‘Pill rolling’
  • Resting tremor, abolished by movement
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5
Q

What kind of rigidity might arise in Parkinsonism?

A
  • Lead pipe rigidity
  • Cog-wheel rigidity
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6
Q

What is lead-pipe rigidity?

A

Resistance in the whole range of movements

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7
Q

How is cogwheel rigidity demonstrated?

A

By slow movement of the wrist

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8
Q

How does bradykinesia manifest in Parkinsons?

A
  • Slow movement
  • Reduced facial expressions and blinking
  • Small writing
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9
Q

What causes bradykinesia in Parkinsons?

A

Low dopamine, and disturbance of other neurotransmitter levels

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10
Q

How does postural instability manifest in Parkinsons?

A
  • Forward flexed shuffling gait
  • Difficulty initiating and terminating
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11
Q

What causes postural instability in Parkinsons?

A

Low dopamine

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12
Q

Why is there low dopamine in Parkinsons?

A

Dopamine producing neurones in the substantia niagra are lost

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13
Q

What % of dopamine producing neurones in the substantia niagra have to be lost to produce clinical signs?

A

50%

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14
Q

What are the non-motor manifestations of Parkinson’s Disease?

A
  • Mood changes
  • Pain
  • Cognitive change
  • Urinary symptoms
  • Sleep disorders
  • Sweating
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15
Q

What sleep disorders might occur in Parkinsons?

A

Patient doesn’t become atonic, and may act out violent dreams

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16
Q

What % of PD patients have dyskinesia at 15 year follow up?

A

94%

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17
Q

What kind of dyskinesia do patients with PD have?

A

Involuntary writhing movements

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18
Q

What might cause the dyskinesia in PD?

A

Treatment side effects

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19
Q

What is meant by somnolenece?

A

Sleep attacks

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20
Q

What is the problem with sleep attacks in Parkinsons?

A

They affect ability to drive

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21
Q

What speech problems does Parkinsons cause?

A

Hypophonia - eventually can hardly speak at all

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22
Q

How is a diagnosis of IPD made?

A
  • Clinical features
  • Exclusion of other causes of Parkinsonism
  • Response to treatment
  • Structural neurological imaging
  • Functional neurological imaging
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23
Q

What are the causes of Parkinsonism, other than IPD?

A
  • Drug induced Parkinsonism
  • Vascular Parkinsonism
  • Progressive supranuclear palsy
  • Multiple Systems Atrophy
  • Corticobasal Degeneration
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24
Q

What can cause drug-induced Parkinsons?

A

Anti-psychotics, e.g. sodium valproate

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25
Q

What are the features of vascular Parkinsonism?

A

Bradykinesa, not so much a tremor

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26
Q

What are the characteristics of progressive supranuclear palsy and multiple systems atrophy?

A

Axial ridigity in the trunk, not so much in the arms

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27
Q

How is multiple systems atrophy treated?

A

Glucocortisone

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28
Q

What kind of Parkinsonism produces normal neurological imaging?

A
  • Idiopathic
  • Drug induced
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29
Q

What functional neurological imaging is used in the diagnosis of IPD?

A
  • SPECT
  • PET
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30
Q

What are the pathological features of Parkinsons Disease?

A
  • Neurodegeneration
  • Lewy bodies
  • Loss of pigment
  • Reduced dopamine
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31
Q

What is meant by loss of pigment in Parkinson’s disease?

A

Degeneration of pigmented cells in substantia niagra

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32
Q

At what % loss of pigment do symptoms arise in Parkinson’s disease?

A

50%

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33
Q

Why do symptoms not occur until there is a 50% loss of pigment in Parkinsons disease?

A

Because other neurones can compensate by working harder, by increasing turnover and upregulating receptors

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34
Q

Draw a diagram illustrating the basal ganglia circuit?

A
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35
Q

What does loss of dopaminergic neurones in the substantia niagra in Parkinsons disease result in?

A

Reduced inhibition in neostriatum, which allows increased production of ACh. This chain of abnormal signalling leads to impaired mobility

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36
Q

Describe the steps in catecholamine synthesis?

A

L-Tyrosine → L-DOPA → Dopamine → Noradrenaline → Adrenaline

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37
Q

What catalyses the conversion of L-Tyrosine to L-DOPA?

A

Tyrosine hydroxylase

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38
Q

What catalyses the conversion of L-DOPA to dopamine?

A

DOPA decarboxylase

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39
Q

What catalyses the conversion of dopamine to noradrenaline?

A

Dopamine B-hydroxylase

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40
Q

What catalyses the conversion of noradrenaline to adrenaline?

A

Phenylethanolamine n-methyltransferase

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41
Q

What is dopamine degraded into?

A
  • 3,4-dihydrophenyl-acetic acid, then to homovanillic acid
  • 3-methoxytyramine, then to homovanillic acid
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42
Q

What catalyses the conversion of dopamine to 3,4-dihydrophenyl-acetic acid?

A
  • Monoamine oxidase
  • Aldehyde dehydrogenase
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43
Q

What catalyses the conversion of 3,4-dihydrophenyl-acetic acid to homovanillic acid?

A

Catechol-O-methyl transferase COMT

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44
Q

What catalyses the conversion of dopamine to 3-methoxytyramine?

A

Catechol-O-methyl transferase COMT

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45
Q

What catalyses the conversion of 3-methoxytyramine to homovanillic acid?

A
  • Monoamine oxidase
  • Aldehyde dehydrogenase
46
Q

Give the steps in neurotransmission

A
  1. Synthesis of neurotransmitter and formation of vesicles
  2. Transport of neurotransmitter down the axon
  3. Action potential travels down axon
  4. Action potential causes calcium to enter, evoking release of neurotransmitter
  5. Neurotransmitter attaches to receptor, exciting or inhibiting the postsynaptic neurone
  6. Separation of the neurotransmitter molecules from receptors
  7. Reuptake of neurotransmitter to be recycled
  8. Vesicles wihout neurotransmitter trasported back to the cell body
47
Q

What is a DAT brain scan?

A

A test to look at the level of dopamine receptor cells in the brain using a small amount of iodine based radioactive material.

The findings are abnormal in Parkinsons disease

48
Q

Is a DAT scan diagnostic of Parkinsons?

A

No

49
Q

What are the drug classes used in the treatment of the movement disorder in Parkinsons disease?

A
  • Levodopa (L-DOPA)
  • Dopamine receptor agonists
  • MAOI type B inhibitors
  • COMT inhibitors
  • Anticholinergics
  • Amantidine
50
Q

Why is L-DOPA used to treat Parkinsons, rather than dopamine?

A

Because L-DOPA can cross the blood brain barrier by active transport, but dopamine cannot

51
Q

What happens to levodopa once it crosses the blood brain barrier?

A

It must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine

52
Q

What is the problem with levodopa in the treatment of Parkinsons diease?

A

If there are fewer remaining dopaminergic cells, there is a less reliable effect of levodopa, and therefore you get motor fluctuations

53
Q

How is levodopa administered?

A

Orally

54
Q

How is levodopa absorbed?

A

By active transport

55
Q

What is the absorption of levodopa in competition with?

A

Amino acids

56
Q

What % of levodopa is inactivated in the intestinal wall?

A

90%

57
Q

What inactivates levodopa in the intestinal wall?

A
  • Monoamine oxidase
  • DOPA decarboxylase
58
Q

What is the half life of levodopa?

A

2 hours

59
Q

What is the result of the short half life of levodopa?

A
  • Short dose interval
  • Fluctuations in blood levels, therefore symptoms
60
Q

What % of levodopa is converted to dopamine in peripheral tissues?

A

9%

61
Q

What % of levodopa is converted to dopamine in peripheral tissues?

A

DOPA decarboxylase

62
Q

What % of levodopa enters the CNS?

A

<1%

63
Q

What limits levodopas entry into the CNS?

A

Competes with amino acids for active transport across the blood brain barrier

64
Q

What is L-DOPA sometimes used in combination with?

A

A peripheral DOPA decarboxylase inhibitor

65
Q

What is co-careldopa?

A

L-DOPA with sinemet

66
Q

What is co-beneldopa?

A

L-DOPA with madopar

67
Q

What is the advantage of giving L-DOPA in combination with a peripheral DOPA decarboxylase inhibitor?

A
  • Reduced dose required
  • Reduced side effects
  • Increased L-DOPA reaching brain
68
Q

Why does a peripheral DOPA decarboxylase inhibitor increase the amount of L-DOPA reaching the brain?

A

It prevents L-DOPA metabolism in the gut and peripheries

69
Q

What are the advantages of L-DOPA?

A
  • Highly efficacious
  • Low side effects
70
Q

What are the side effects of L-DOPA?

A
  • Nausea/anorexia
  • Hypotension
  • Psychosis
  • Tachycardia
71
Q

Why does L-DOPA cause nausea/anorexia?

A

Due to its effect on vomiting centres

72
Q

Does L-DOPA cause central or peripheral hypertension?

A

Both

73
Q

What are the disadvantages of L-DOPA?

A
  • Precursor, so needs enzyme conversion
  • Long term problems
74
Q

What are the long term effects of L-DOPA?

A
  • Loss of efficacy
  • Involuntary movements
  • Motor complications, including dyskinesia, dystonia, and freezing
75
Q

Why is there a loss of efficacy with long term L-DOPA use?

A

Because it is only effective in the presence of dopaminergic neurones, which reduce as Parkinsons progresses

76
Q

What does L-DOPA interact with?

A
  • Pyridoxine
  • MAOIs
77
Q

What effect does pyridoxine have on L-DOPA?

A

It increases peripheral resistance of L-DOPA

78
Q

What happens when MAOIs are given with L-DOPA?

A

RIsk hypertensive crisis

79
Q

What are the categories of dopamine receptor agonists?

A
  • Ergot derived
  • Non-ergot
  • Patch
  • Subcutaneous
80
Q

Give three examples of ergot derived dopamine receptor agonists

A
  • Bromocryptine
  • Pergolide
  • Cabergoline
81
Q

Give two examples of non ergot dopamine receptor agonists

A
  • Ropinirole
  • Pramipexole
82
Q

Give an example of a patch dopamine receptor agonist

A

Rotigotine

83
Q

Give an example of a subcutaneous dopamine receptor agonist

A

Apomorphine

84
Q

How can dopamine receptor therapy be given?

A
  • De novo therapy
  • Add on therapy
85
Q

What patients are given apomorphine?

A

Only those with severe motor fluctations

86
Q

What are the advantages of dopamine receptor agonists?

A
  • Direct acting
  • Less dyskinesias/motor complications
  • Possible neuroprotection
87
Q

What are the disadvantages of dopamine receptor agonists?

A
  • Less efficacy than L-DOPA
  • Causes impulse control disorders
  • More psychiatric side effects, which are dose limiting
  • Expensive
88
Q

What are the features of impulse control disorders?

A
  • Pathological gambling
  • Hypersexuality
  • Compulsive shopping
  • Desire to increase dosage
  • Punding
89
Q

What are the side effects of dopamine receptor agonists?

A
  • Sedation
  • Hallucinations
  • Confusion
  • Nausea
  • Hypotension
90
Q

What is the function of monoamine oxidase B?

A

It metabolises dopamine

91
Q

Where does monoamine oxidase B action predominate?

A

In dopamine containing regions in the brain

92
Q

What effect do monoamine oxidase B have on dopamine?

A

They enhance it

93
Q

Give two examples of monoamine oxidase B inhibitors

A
  • Selegiline
  • Rasagaline
94
Q

Can monoamine oxidase B inhibitors be used alone?

A

Yes

95
Q

What effect do monoamine oxidase B inhibitors have on L-DOPA?

A

They prolong the action

96
Q

What effect do monoamine oxidase B inhibitors have on Parkinsons symptoms?

A
  • Smooths out motor response
  • May be neuroprotective
97
Q

Give two examples of catechol-O-methyl transferase (COMT) inhibitors

A
  • Entacapone
  • Tolcapone
98
Q

Do COMT inhibitors cross the blood brain barrier?

A
  • Entacapone doesn’t
  • Tolcapone does, but its main effect is peripheral
99
Q

What effect do COPT inhibitors have?

A

They reduce peripheral breakdown of L-DOPA to 3-O-methyldopa, which competes with 3-O-methyldopa active transport into the CNS

100
Q

Can COMT inhibitors be used alone?

A

No

101
Q

What are COMT inhibitors used in combination with?

A

L-DOPA and a peripheral DOPA decarboxylase inhibitor, e.g. Stalevo

102
Q

What effect do COMT inhibitors have on L-DOPA?

A

It prolonges the motor response to L-DOPA, and reduces symptoms of ‘wearing off’

103
Q

What is the principle behind the use of anticholinergics in Parkinsons?

A

Acetylcholine may have antagonistic effects to dopamine

104
Q

Give three examples of anticholinergics

A
  • Trihexyphenidydyl
  • Orphenadrine
  • Procyclidine
105
Q

What are the advantages of anticholinergics?

A
  • Treats the tremor
  • Doesn’t act via dopamine systems
106
Q

What are the disadvantages of anticholinergics?

A
  • No effect of bradykinesia
  • Side effects, including confusion and drowsiness
107
Q

What is the mechanism of action of amantadine?

A

Uncertain, but possible enhanced dopamine release or anticholinergic NMDA inhibition

108
Q

What are the advantages of amantadine?

A

Few side effects

109
Q

What are the disadvantages of amantadine?

A
  • Poorly effective
  • Little effect on tremor
110
Q

When is surgery of value in Parkinsons disease?

A

In highly selected cases;

  • Dopamine responsive
  • Significant side effects with L-DOPA
  • No psychiatric illness
111
Q

What is done in surgery for Parkinsons?

A
  • A lesion is made, in the thalamus for a tremor, or in the globus pallidus interna for dyskinesias
  • Deep brain stimulation to the subthalamic nucleus
112
Q
A

ESA 5 - Pharmacology (28 decks)

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