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PN3312 > Parkinson's Disease > Flashcards

Parkinson's Disease Flashcards

1
Q

What are the main components of movement control?

A

Hierarchical: Cortex -> Brainstem -> Spinal cord

The basal ganglia and the cerebellum also modulate movement through the thalamus

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2
Q

What are the components of the basal ganglia?

A
  • Caduate nucleus + putamen make the striatum

- Globus pallidus and substantia nigra (implicated in Parkinson’s)

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3
Q

What is the role of the basal ganglia?

A
  • Recieves input from the cortex which it relays through the putamen and globus pallidus
  • Output on the cortex and spinal cord
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4
Q

What is the direct pathway?

A
  • Recieves dopaminergic input from the substantia nigra which binds to D1 receptors and facilitates movement
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5
Q

What is the indirect pathway?

A
  • Dopaminergic input on D2 receptors

- Inhibits movement (specifically competing motor patterns)

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6
Q

What are the symptoms of Parkinson’s Disease?

A
  • Resting tremor
  • Akinesia (impaired movement initiation)
  • Bradykinesia (slowing)
  • Rigidity due to increased muscle tone
  • Postural instability
  • Mask-like facial expressions
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7
Q

What is the pathology of Parkinson’s?

A
  • Deficiency of dopamine in the striatum
  • Dopaminergic neurons of the substantia nigra degenerate (symptoms only appear after 60-80% loss)
  • Increased inhibition of movement through D2 indirect pathway
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8
Q

What are the known causes of Parkinsons?

A
  • Rare hereditary forms
  • Environmental factors
  • Trauma
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9
Q

What drug is used to model Parkinsons? Why?

A
  • MPTP given to heroin addicts, however contaminated with MPPP which is converted to MPP+ by monoamine oxidase
  • Taken up by dopaminergic neurons in the motor regions causing severe Parkinsons
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10
Q

How is dopamine synthesised at the synapse?

A
  • From L-tyrosine which is converted to L-Dopa by tyrosine hydroxylase in a rate limiting step
  • L-Dopa decarboxylated to dopamine only after crossing BBB
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11
Q

How is L-Dopa believed to function as a drug?

A
  • Absorbed by the small intestine with a 2 hour half life (relatively short)
  • Broken down by decarboxylation in the brain to create more dopamine
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12
Q

How effective is L-Dopa as a treatment?

A

Relatively good

  • 80% of patients show improvement
  • 20% restored to normal function
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13
Q

Why is L-Dopa typically only used much later in Parkinson’s treatment?

A

Effectiveness declines quickly due to disease progression and down-regulation of receptors

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14
Q

What are the possible side effects of L-DOPA treatment?

A
  • Dyskinesia (involuntary movements) typically after 2 years of therapy relating to L-Dopa peaks
  • On/Off effect due to rapid fluctuations of L-Dopa relating to its short half-life
  • Nau
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15
Q

What are the possible accute side-effects of L-Dopa treatment?

A

Usually occur in the first weeks of treatment before dissapearing

  • Nausea (can be treated with peripheral DA antagonist0
  • Hypertension (can be an issue with patients already on anti-hypertensives)
  • Schizophrenia-like dellusions and hallucinations
  • Confusion, insomnia and nightmares
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16
Q

What are L-DOPA combination therapies?

A

Most L-Dopa broken down at the periphery by DOPA-decarboxylase

  • Can be inhibited by co-administering carbidopa (doesn’t cross the BBB)
  • Can administer 10 fold less L-DOPA and prevents side effects associated with peropheral dopamine
17
Q

How is dopamine broken down at the synapse?

A

By monoamine oxidase (MAO) or COMT to make homovanillic acid (HVA)

18
Q

How can monoamine oxidase-B inhibition be used to treat Parkinsons?

A

Seregiline/Rasagiline

  • Selectivity for MAO-B limits peripheral side effects
  • Increases interneuronal dopamine levels
  • Can be used as early monotherapies to increase time before L-DOPA or administered in combination
19
Q

How can inhibition of COMT be used to treat Parkinsons?

A
  • Talcapone crosses BBB, inhibits COMT which breaks down dopamine and L-Dopa
  • Used in combination with L-DOPA and carbidopa and reduces on-off effect by reducing fluctuations inn L_DOPA levels
20
Q

How can D2 dopamine receptor agonists be used to treat Parkinsons?

A
  • Bromocriptine is a potent D2 agonist, however has a long plasma half life (6/8 hours) and so is administered less frequently
  • Lisuride is a D1/D2 agonist which is more potent but shorter acting
    Both used as early monotherapies or in combination, similar side effects to high L-DOPA levels
21
Q

What is apomorphine?

A
  • Relatively non-selective DA receptor agonist
  • Due to emitic properties (vomiting) and short half-life administered subcutaneously
  • Rapid effect in 3-20mins with brief duration, used to combat sudden attacks

PN3312 (11 decks)

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